Hepatitis C virus inhibitors

ABSTRACT

The present disclosure is generally directed to antiviral compounds, and more specifically directed to compounds which can inhibit the function of the NS5A protein encoded by Hepatitis C virus (HCV), compositions comprising such compounds, and methods for inhibiting the function of the NS5A protein.

CROSS-REFERENCE TO RELATED APPLICATIONS

This Divisional application claims the benefit of U.S. Ser. No.12/974,069 filed Dec. 21, 2010, now allowed, which in turn claims thebenefit of U.S. Provisional Application U.S. Ser. No. 61/290,898 filedDec. 30, 2009, now expired.

FIELD OF THE DISCLOSURE

The present disclosure is generally directed to antiviral compounds, andmore specifically directed to compounds which can inhibit the functionof the NS5A protein encoded by Hepatitis C virus (HCV), compositionscomprising such compounds, and methods for inhibiting the function ofthe NS5A protein.

BACKGROUND OF THE DISCLOSURE

The present disclosure is generally directed to antiviral compounds, andmore specifically directed to compounds which can inhibit the functionof the NS5A protein encoded by Hepatitis C virus (HCV), compositionscomprising such compounds, and methods for inhibiting the function ofthe NS5A protein.

HCV is a major human pathogen, infecting an estimated 170 millionpersons worldwide—roughly five times the number infected by humanimmunodeficiency virus type 1. A substantial fraction of these HCVinfected individuals develop serious progressive liver disease,including cirrhosis and hepatocellular carcinoma.

The current standard of care for HCV, which employs a combination ofpegylated-interferon and ribavirin, has a non-optimal success rate inachieving sustained viral response and causes numerous side effects.Thus, there is a clear and long-felt need to develop effective therapiesto address this undermet medical need.

HCV is a positive-stranded RNA virus. Based on a comparison of thededuced amino acid sequence and the extensive similarity in the 5′untranslated region, HCV has been classified as a separate genus in theFlaviviridae family. All members of the Flaviviridae family haveenveloped virions that contain a positive stranded RNA genome encodingall known virus-specific proteins via translation of a single,uninterrupted, open reading frame.

Considerable heterogeneity is found within the nucleotide and encodedamino acid sequence throughout the HCV genome due to the high error rateof the encoded RNA dependent RNA polymerase which lacks a proof-readingcapability. At least six major genotypes have been characterized, andmore than 50 subtypes have been described with distribution worldwide.The clinical significance of the genetic heterogeneity of HCV hasdemonstrated a propensity for mutations to arise during monotherapytreatment, thus additional treatment options for use are desired. Thepossible modulator effect of genotypes on pathogenesis and therapyremains elusive.

The single strand HCV RNA genome is approximately 9500 nucleotides inlength and has a single open reading frame (ORF) encoding a single largepolyprotein of about 3000 amino acids. In infected cells, thispolyprotein is cleaved at multiple sites by cellular and viral proteasesto produce the structural and non-structural (NS) proteins. In the caseof HCV, the generation of mature non-structural proteins (NS2, NS3,NS4A, NS4B, NS5A, and NS5B) is effected by two viral proteases. Thefirst one is believed to be a metalloprotease and cleaves at the NS2-NS3junction; the second one is a serine protease contained within theN-terminal region of NS3 (also referred to herein as NS3 protease) andmediates all the subsequent cleavages downstream of NS3, both in cis, atthe NS3-NS4A cleavage site, and in trans, for the remaining NS4A-NS4B,NS4B-NS5A, NS5A-NS5B sites. The NS4A protein appears to serve multiplefunctions by both acting as a cofactor for the NS3 protease andassisting in the membrane localization of NS3 and other viral replicasecomponents. The formation of a NS3-NS4A complex is necessary for properprotease activity resulting in increased proteolytic efficiency of thecleavage events. The NS3 protein also exhibits nucleoside triphosphataseand RNA helicase activities. NS5B (also referred to herein as HCVpolymerase) is a RNA-dependent RNA polymerase that is involved in thereplication of HCV with other HCV proteins, including NS5A, in areplicase complex.

Compounds useful for treating HCV-infected patients are desired whichselectively inhibit HCV viral replication. In particular, compoundswhich are effective to inhibit the function of the NS5A protein aredesired. The HCV NS5A protein is described, for example, in thefollowing references: S. L. Tan, et al., Virology, 284:1-12 (2001);K.-J. Park, et al., J. Biol. Chem., 30711-30718 (2003); T. L.Tellinghuisen, et al., Nature, 435, 374 (2005); R. A. Love, et al., J.Virol, 83, 4395 (2009); N. Appel, et al., J. Biol. Chem., 281, 9833(2006); L. Huang, J. Biol. Chem., 280, 36417 (2005); C. Rice, et al.,World Patent Application WO-2006093867, Sep. 8, 2006.

SUMMARY OF THE DISCLOSURE

The present disclosure provides compounds which selectively inhibit HCVviral replication, as characterized by Formula (I):

or a stereoisomer or a pharmaceutically acceptable salt or solvatethereof, wherein:

Q¹, Q², Q³, Q⁴, Q⁵, Q⁶, Q⁷, and Q⁸ are each independently selected fromCR^(w) and N; wherein each R^(w) is independently selected fromhydrogen, C₁₋₆ alkoxy, C₁₋₄ alkyl, and halo;

L is a five-membered heterocyclyl group selected from the groupconsisting of

wherein R^(x) at each occurrence is independently hydrogen, halogen, orC₁₋₄ alkyl optionally substituted by —C(O)OR³ or —NMe₂, wherein R^(y) ateach occurrence is independently hydrogen or C₁₋₄ alkyl, and wherein R³is hydrogen or C₁₋₄ alkyl;

R¹ and R² are independently selected from cycloalkyl, heteroaryl,heterocyclyl, C₁₋₆ alkoxy, —NHR^(p), and alkyl, wherein said alkyl isoptionally substituted by one, two, or three substituents independentlyselected from aryl, alkenyl, cycloalkyl, heterocyclyl, heteroaryl,—OSi(R^(q))₃, —OR⁴, —SR⁵, —C(O)OR⁶, —NHC(O)R⁷, —NR^(a)R^(b), and—C(O)NR^(c)R^(d),

wherein R^(p) is heterocyclyl,

wherein R^(q) at each occurrence is independently C₁₋₄ alkyl or phenyl,

wherein any said aryl or heteroaryl may optionally be substituted withone or more substituents independently selected from C₁₋₄ alkyl, C₁₋₄haloalkyl, arylalkyl, heterocyclyl, heterocyclylalkyl, halogen, cyano,nitro, —OR⁴, —C(O)OR⁶, —NR^(a)R^(b), (NR^(a)R^(b))alkyl, and—OP(O)(OH)(OR⁵), and

wherein any said cycloalkyl or heterocyclyl may optionally be fused ontoan aromatic ring and may optionally be substituted with one or moresubstituents independently selected from C₁₋₄ alkyl, halogen, aryl,arylalkyl, heteroarylalkyl, fused cyclopropyl, —NR^(a)R^(b), oxo, —OR⁴,—C(O)OR⁶, and —C(O)R⁷;

R⁴ is hydrogen, C₁₋₆ alkyl, or benzyl;

R⁵ is hydrogen or C₁₋₄ alkyl;

R⁶ at each occurrence is independently C₁₋₆ alkyl, aryl, benzyl, orheteroaryl;

R⁷ at each occurrence is independently selected from —OR⁸, C₁₋₆ alkyl,C₁₋₆ haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and -L¹-R¹¹,wherein said aryl and heteroaryl may optionally be substituted by one ormore substituents independently selected from C₁₋₄ alkyl, halogen, —OR⁹,and —NR^(a)R^(b), and wherein said cycloalkyl and heterocyclyl mayoptionally be substituted by one or more substituents independentlyselected from C₁₋₄ alkyl, —C(O)OR¹⁰, fused cyclopropyl, cyano, oxo,phenyl —NR^(a)R^(b), -L¹-R¹¹, C(O)R¹¹, and —C(O)-L¹-R¹¹;

-   -   R⁸ is C₁₋₆ alkyl, phenyl optionally substituted with a halogen,        arylalkyl, —(C₁₋₃ alkylene)-C(O)OR¹⁰, or —(C₁₋₃        alkylene)-O—(C₁₋₃ alkylene);

R⁹ is hydrogen, C₁₋₆ alkyl, or C₁₋₄ haloalkyl;

R¹⁰ is hydrogen, C₁₋₆ alkyl, phenyl, or benzyl;

L¹ is C₁₋₂ alkylene optionally substituted by one or two substituentsindependently selected from C₁₋₄ alkyl, —OR¹², —OC(O)R¹³, —NR^(a)R^(b),phenyl, and oxo;

R¹¹ is C₁₋₆ alkyl, C₁₋₄ haloalkyl, cycloalkyl, heterocyclyl, aryl,heteroaryl, —OR⁸, or —NR^(a)R^(b), wherein said aryl or heteroaryl mayoptionally be substituted by one or more substituents independentlyselected from C₁₋₄ alkyl, halogen, —OR⁹, nitro, cyano, and —NR^(a)R^(b),and wherein said cycloalkyl or heterocyclyl may optionally besubstituted by one or more substituents independently selected from C₁₋₄alkyl, benzyl, phenyl, halogen, —OR⁹, oxo, fused cyclopropyl,—NR^(a)R^(b), —C(O)R¹⁰, and —C(O)OR¹⁰;

R¹² is hydrogen, C₁₋₄ alkyl, aryl, or heteroaryl, wherein said aryl orheteroaryl may optionally be substituted by one or more substituentsindependently selected from C₁₋₄ alkyl, halogen, and —OR⁹;

R¹³ is C₁₋₄ alkyl or aryl;

R^(a) and R^(b) are independently selected from hydrogen, C₁₋₆ alkyl,cycloalkyl, arylalkyl, heteroaryl, heterocyclyl, —C(O)R¹⁴, —C(O)OR¹⁵,—C(O)NR^(c)R^(d), and (NR^(c)R^(d))alkyl, or alternatively, R^(a) andR^(b), together with the nitrogen atom to which they are attached, forma five- or six-membered ring or bridged bicyclic ring structure, whereinsaid five- or six-membered ring or bridged bicyclic ring structureoptionally may contain one or two additional heteroatoms independentlyselected from nitrogen, oxygen, and sulfur and may contain one, two, orthree substituents independently selected from C₁₋₆ alkyl, C₁₋₄haloalkyl, aryl, halogen, and —OR⁹;

R^(c) and R^(d) are independently selected from hydrogen, C₁₋₄ alkyl,benzyl, and cycloalkyl;

R¹⁴ is C₁₋₄ alkyl, arylalkyl, aryl, or heteroaryl, each optionallysubstituted by one, two or three substituents independently selectedfrom C₁₋₄ alkyl, halogen, and —OR⁹; and

R¹⁵ is C₁₋₆ alkyl, arylalkyl, or C₁₋₄ haloalkyl.

The compounds of the present disclosure can be effective to inhibit thefunction of the HCV NS5A protein. In particular, the compounds of thepresent disclosure can be effective to inhibit the HCV 1b genotype ormultiple genotypes of HCV. Therefore, this disclosure also encompasses:(1) compositions comprising a compound of Formula (I), or apharmaceutically acceptable salt or solvate thereof, and apharmaceutically acceptable carrier; and (2) a method of treating an HCVinfection in a patient, comprising administering to the patient atherapeutically effective amount of a compound of Formula (I), or apharmaceutically acceptable salt or solvate thereof.

DETAILED DESCRIPTION OF THE DISCLOSURE

In a first aspect of the present disclosure compounds of Formula (I) areprovided:

In a first embodiment of the first aspect, the present disclosureprovides a compound of Formula (I), or a stereoisomer or apharmaceutically acceptable salt or solvate thereof, wherein:

Q¹, Q², Q³, Q⁴, Q⁵, Q⁶, Q⁷, and Q⁸ are each independently selected fromCR^(w) and N; wherein each R^(w) is independently selected fromhydrogen, C₁₋₆ alkoxy, C₁₋₄ alkyl, and halo;

L is a five-membered heterocyclyl group selected from the groupconsisting of

wherein R^(x) at each occurrence is independently hydrogen, halogen, orC₁₋₄ alkyl optionally substituted by —C(O)OR³ or —NMe₂, wherein R^(y) ateach occurrence is independently hydrogen or C₁₋₄ alkyl, and wherein R³is hydrogen or C₁₋₄ alkyl;

R¹ and R² are independently selected from cycloalkyl, heteroaryl,heterocyclyl, C₁₋₆ alkoxy, —NHR^(p), and alkyl, wherein said alkyl isoptionally substituted by one, two, or three substituents independentlyselected from aryl, alkenyl, cycloalkyl, heterocyclyl, heteroaryl,—OSi(R^(q))₃, —OR⁴, —SR⁵, —C(O)OR⁶, —NHC(O)R⁷, —NR^(a)R^(b), and—C(O)NR^(c)R^(d),

wherein R^(p) is heterocyclyl,

wherein R^(q) at each occurrence is independently C₁₋₄ alkyl or phenyl,

wherein any said aryl or heteroaryl may optionally be substituted withone or more substituents independently selected from C₁₋₄ alkyl, C₁₋₄haloalkyl, arylalkyl, heterocyclyl, heterocyclylalkyl, halogen, cyano,nitro, —OR⁴, —C(O)OR⁶, —NR^(a)R^(b), (NR^(a)R^(b))alkyl, and—OP(O)(OH)(OR⁵), and

wherein any said cycloalkyl or heterocyclyl may optionally be fused ontoan aromatic ring and may optionally be substituted with one or moresubstituents independently selected from C₁₋₄ alkyl, halogen, aryl,arylalkyl, heteroarylalkyl, fused cyclopropyl, —NR^(a)R^(b), oxo, —OR⁴,—C(O)OR⁶, and —C(O)R⁷;

R⁴ is hydrogen, C₁₋₆ alkyl, or benzyl;

R⁵ is hydrogen or C₁₋₄ alkyl;

R⁶ at each occurrence is independently C₁₋₆ alkyl, aryl, benzyl, orheteroaryl;

R⁷ at each occurrence is independently selected from —OR⁸, C₁₋₆ alkyl,C₁₋₆ haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and -L¹-R¹¹,wherein said aryl and heteroaryl may optionally be substituted by one ormore substituents independently selected from C₁₋₄ alkyl, halogen, —OR⁹,and —NR^(a)R^(b), and wherein said cycloalkyl and heterocyclyl mayoptionally be substituted by one or more substituents independentlyselected from C₁₋₄ alkyl, —C(O)OR¹⁰, fused cyclopropyl, cyano, oxo,phenyl, —NR^(a)R^(b), -L¹-R¹¹, C(O)R¹¹, and —C(O)-L¹-R¹¹;

R⁸ is C₁₋₆ alkyl, phenyl optionally substituted with a halogen,arylalkyl, —(C₁₋₃ alkylene)-C(O)OR¹⁰, or —(C₁₋₃ alkylene)-O—(C₁₋₃alkylene);

R⁹ is hydrogen, C₁₋₆ alkyl, or C₁₋₄ haloalkyl;

R¹⁰ is hydrogen, C₁₋₆ alkyl, phenyl, or benzyl;

L¹ is C₁₋₂ alkylene optionally substituted by one or two substituentsindependently selected from C₁₋₄ alkyl, —OR¹², —OC(O)R¹³, —NR^(a)R^(b),phenyl, and oxo;

R¹¹ is C₁₋₆ alkyl, C₁₋₄ haloalkyl, cycloalkyl, heterocyclyl, aryl,heteroaryl, —OR⁸, or —NR^(a)R^(b), wherein said aryl or heteroaryl mayoptionally be substituted by one or more substituents independentlyselected from C₁₋₄ alkyl, halogen, —OR⁹, nitro, cyano, and —NR^(a)R^(b),and wherein said cycloalkyl or heterocyclyl may optionally besubstituted by one or more substituents independently selected from C₁₋₄alkyl, benzyl, phenyl, halogen, —OR⁹, oxo, fused cyclopropyl,—NR^(a)R^(b), —C(O)R¹⁰, and —C(O)OR¹⁰;

R¹² is hydrogen, C₁₋₄ alkyl, aryl, or heteroaryl, wherein said aryl orheteroaryl may optionally be substituted by one or more substituentsindependently selected from C₁₋₄ alkyl, halogen, and —OR⁹;

R¹³ is C₁₋₄ alkyl or aryl;

R^(a) and R^(b) are independently selected from hydrogen, C₁₋₆ alkyl,cycloalkyl, arylalkyl, heteroaryl, heterocyclyl, —C(O)R¹⁴, —C(O)OR¹⁵,—C(O)NR^(c)R^(d), and (NR^(c)R^(d))alkyl, or alternatively, R^(a) andR^(b), together with the nitrogen atom to which they are attached, forma five- or six-membered ring or bridged bicyclic ring structure, whereinsaid five- or six-membered ring or bridged bicyclic ring structureoptionally may contain one or two additional heteroatoms independentlyselected from nitrogen, oxygen, and sulfur and may contain one, two, orthree substituents independently selected from C₁₋₆ alkyl, C₁₋₄haloalkyl, aryl, halogen, and —OR⁹;

R^(c) and R^(d) are independently selected from hydrogen, C₁₋₄ alkyl,benzyl, and cycloalkyl;

R¹⁴ is C₁₋₄ alkyl, arylalkyl, aryl, or heteroaryl, each optionallysubstituted by one, two or three substituents independently selectedfrom C₁₋₄ alkyl, halogen, and —OR⁹; and

R¹⁵ is C₁₋₆ alkyl, arylalkyl, or C₁₋₄ haloalkyl.

In a second embodiment of the first aspect, the present disclosureprovides a compound of Formula (I), or a stereoisomer or apharmaceutically acceptable salt or solvate thereof, wherein:

L is a five-membered heterocyclyl group selected from the groupconsisting of

wherein R^(x) at each occurrence is independently hydrogen, halogen, orC₁₋₄ alkyl optionally substituted by —C(O)OR³ or —NMe₂, wherein R^(y) ateach occurrence is independently hydrogen or C₁₋₄ alkyl, and wherein R³is hydrogen or C₁₋₄ alkyl;

R¹ and R² are independently selected from the group consisting of:

wherein:

n is 0, 1, 2, or 3;

R¹⁶ at each occurrence is independently C₁₋₄ alkyl, —OR⁴, or oxo;

R¹⁷ at each occurrence is independently hydrogen or —C(O)R⁷;

R¹⁸ is C₁₋₆ alkyl optionally substituted by —OR⁴ or —SR⁵;

R⁴ is hydrogen or C₁₋₆ alkyl;

R⁵ is C₁₋₄ alkyl;

R⁷ at each occurrence is independently selected from —OR⁸, C₁₋₆ alkyl,C₁₋₆ haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and -L¹-R¹¹,wherein said aryl and heteroaryl may optionally be substituted by one ormore, preferably one to three, substituents independently selected fromC₁₋₄ alkyl, halogen, —OR⁹, and —NR^(a)R^(b), and wherein said cycloalkyland heterocyclyl may optionally be substituted by one or more,preferably one to three, substituents independently selected from C₁₋₄alkyl, —C(O)OR¹⁰, oxo, phenyl, fused cyclopropyl, —NR^(a)R^(b), -L¹-R¹¹,—C(O)R¹¹, and —C(O)-L¹-R¹¹;

R⁸ is C₁₋₆ alkyl or arylalkyl;

R⁹ is hydrogen, C₁₋₆ alkyl, or C₁₋₄ haloalkyl;

R¹⁰ is hydrogen, phenyl, C₁₋₆ alkyl, or benzyl;

L¹ is C₁₋₂ alkylene optionally substituted by one or two substituentsindependently selected from C₁₋₄ alkyl, —OR¹², —OC(O)R¹³, —NR^(a)R^(b),phenyl, and oxo;

R¹¹ is C₁₋₆ alkyl, C₁₋₄ haloalkyl, cycloalkyl, heterocyclyl, aryl,heteroaryl, or —NR^(a)R^(b), wherein said aryl or heteroaryl mayoptionally be substituted by one or more, preferably one to three,substituents independently selected from C₁₋₄ alkyl, halogen, —OR⁹,nitro, cyano, and —NR^(a)R^(b), and wherein said cycloalkyl orheterocyclyl may optionally be substituted by one or more, preferablyone to three, substituents independently selected from C₁₋₄ alkyl,benzyl, halogen, —OR⁹, oxo, phenyl, fused cyclopropyl, —NR^(a)R^(b),—C(O)R¹⁰, and —C(O)OR¹⁰;

R¹² is hydrogen, C₁₋₄ alkyl, aryl, or heteroaryl, wherein said aryl orheteroaryl may optionally be substituted by one or more, preferably oneto three, substituents independently selected from C₁₋₄ alkyl, halogen,and —OR⁹;

R¹³ is C₁₋₄ alkyl or aryl;

R^(a) and R^(b) are independently selected from hydrogen, C₁₋₆ alkyl,cycloalkyl, arylalkyl, heteroaryl, heterocyclyl, —C(O)R¹⁴, —C(O)OR¹⁵,—C(O)NR^(c)R^(d), and (NR^(c)R^(d))alkyl, or alternatively, R^(a) andR^(b), together with the nitrogen atom to which they are attached, forma five- or six-membered ring or bridged bicyclic ring structure, whereinsaid five- or six-membered ring or bridged bicyclic ring structureoptionally may contain one or two additional heteroatoms independentlyselected from nitrogen, oxygen, and sulfur and may contain one, two, orthree substituents independently selected from C₁₋₆ alkyl, C₁₋₄haloalkyl, aryl, halogen, and —OR⁹;

R^(c) and R^(d) are independently selected from hydrogen, C₁₋₄ alkyl,benzyl, and cycloalkyl;

R¹⁴ is C₁₋₄ alkyl, arylalkyl, aryl, or heteroaryl, each optionallysubstituted by one, two or three substituents independently selectedfrom C₁₋₄ alkyl, halogen, and —OR⁹; and

R¹⁵ is C₁₋₆ alkyl, arylalkyl, or C₁₋₄ haloalkyl.

In a third embodiment of the first aspect, the present disclosureprovides a compound of Formula (I), or a stereoisomer or apharmaceutically acceptable salt or solvate thereof, wherein:

L is a five-membered heterocyclyl group selected from the groupconsisting of

wherein R^(x) at each occurrence is independently hydrogen, halogen, orC₁₋₄ alkyl optionally substituted by —C(O)OR³ or —NMe₂, wherein R^(y) ateach occurrence is independently hydrogen or C₁₋₄ alkyl, and wherein R³is hydrogen or C₁₋₄ alkyl;

R¹ and R² are independently selected from the group consisting of:

wherein:

n is 0, 1, 2, or 3;

R¹⁶ at each occurrence is independently C₁₋₄ alkyl, —OR⁴, or oxo;

R¹⁷ at each occurrence is independently hydrogen or —C(O)R⁷;

R¹⁸ is C₁₋₆ alkyl optionally substituted by —OR⁴ or —SR⁵;

R⁴ is hydrogen or C₁₋₆ alkyl;

R⁵ is C₁₋₄ alkyl;

R⁷ at each occurrence is independently selected from the groupconsisting of —OCH₂Ph, —OC(CH₃)₃, methyl, ethyl, isopropyl, —CH₂Ph,cyclopropyl, cyclobutyl, phenyl,

In a fourth embodiment of the first aspect, the present disclosureprovides a compound of Formula (Ia):

or a stereoisomer or a pharmaceutically acceptable salt or solvatethereof, wherein:

R^(x) is hydrogen, methyl, —CH₂C(O)OR³, or —CH₂NMe₂, wherein R³ ishydrogen or C₁₋₄ alkyl;

R¹ and R² are each independently

R¹⁷ at each occurrence is independently hydrogen or —C(O)R⁷;

R⁷ at each occurrence is independently —OR⁸ or benzyl; and

R⁸ is C₁₋₄ alkyl or benzyl.

In a fifth embodiment of the first aspect, the present disclosureprovides a compound of Formula (Ib):

or a stereoisomer or a pharmaceutically acceptable salt or solvatethereof, wherein:

R^(x) is hydrogen or C₁₋₄ alkyl;

R¹ and R² are independently selected from:

wherein:

R¹⁶ is hydrogen, OH, or —OR⁴, wherein R⁴ is hydrogen or C₁₋₄ alkyl;

R¹⁷ at each occurrence is independently hydrogen or —C(O)R⁷;

R⁷ at each occurrence is independently selected from —OR⁸, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, heterocyclyl, aryl, heteroaryl, and-L¹-R¹¹, wherein said aryl and heteroaryl may optionally be substitutedby one, two, or three substituents independently selected from C₁₋₄alkyl, halogen, —OR⁹, and —NR^(a)R^(b), and wherein said cycloalkyl andheterocyclyl may optionally be substituted by one, two, or threesubstituents independently selected from C₁₋₄ alkyl, —C(O)OR¹⁰, oxo,phenyl, fused cyclopropyl, —NR^(a)R^(b), -L¹-R¹¹, —C(O)R¹¹, and—C(O)-L¹-R¹¹;

R⁸ is C₁₋₄ alkyl or benzyl;

R⁹ is hydrogen or C₁₋₄ alkyl;

R¹⁰ is C₁₋₄ alkyl, phenyl, or benzyl;

L¹ is C₁₋₂ alkylene optionally substituted by one or two substituentsindependently selected from C₁₋₄ alkyl, —OR¹², —OC(O)R¹³, —NR^(a)R^(b),phenyl, and oxo;

R¹¹ is C₁₋₄ alkyl, C₁₋₄ haloalkyl, cycloalkyl, heterocyclyl, aryl,heteroaryl, or —NR^(a)R^(b), wherein said aryl or heteroaryl mayoptionally be substituted by one, two, or three substituentsindependently selected from C₁₋₄ alkyl, halogen, —OR⁹, and —NR^(a)R^(b),and wherein said cycloalkyl or heterocyclyl may optionally besubstituted by one, two, or three substituents independently selectedfrom C₁₋₄ alkyl, benzyl, phenyl, halogen, —OR⁹, oxo, fused cyclopropyl,—NR^(a)R^(b), —C(O)R¹⁰, and —C(O)OR¹⁰;

R¹² is hydrogen, C₁₋₄ alkyl, aryl, or heteroaryl, wherein said aryl orheteroaryl may optionally be substituted by one or more, preferably oneto three, substituents independently selected from C₁₋₄ alkyl, halogen,and —OR⁹;

R¹³ is C₁₋₄ alkyl;

R^(a) and R^(b) are independently selected from hydrogen, C₁₋₄ alkyl,—C(O)R¹⁴, or alternatively, R^(a) and R^(b), together with the nitrogenatom to which they are attached, form a five- or six-membered ring,wherein said five- or six-membered ring optionally may contain oneadditional heteroatom selected from nitrogen, oxygen, and sulfur and maycontain one, two, or three substituents independently selected from C₁₋₄alkyl, C₁₋₄ haloalkyl, aryl, halogen, and —OR⁹;

R¹⁴ is C₁₋₄ alkyl;

R^(17a) is heteroarylalkyl; and

R¹⁸ is C₁₋₄ alkyl optionally substituted by —OR⁴ or —SR⁵, wherein R⁴ andR⁵ are each independently C₁₋₄ alkyl.

In a sixth embodiment of the first aspect, the present disclosureprovides a compound of Formula (Ib), or a stereoisomer or apharmaceutically acceptable salt or solvate thereof, wherein:

R^(x) is hydrogen;

R¹ and R² are independently selected from:

wherein:

R¹⁶ is hydrogen, OH, or —OR⁴, wherein R⁴ is hydrogen or C₁₋₄ alkyl;

R¹⁷ at each occurrence is independently hydrogen or —C(O)R⁷;

R⁷ is selected from the group consisting of —OCH₂Ph, —OC(CH₃)₃, methyl,ethyl, —CH₂Ph, cyclopropyl, cyclobutyl, phenyl,

and

R^(17a) is

In a seventh embodiment of the first aspect, the present disclosureprovides a compound of Formula (Ic):

or a stereoisomer or a pharmaceutically acceptable salt or solvatethereof, wherein:

R¹ and R² are independently selected from:

R¹⁷ at each occurrence is independently hydrogen or —C(O)R⁷;

R⁷ at each occurrence is independently selected from the groupconsisting of —OR⁸, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, benzyl, aryl,heterocyclyl, heteroaryl, and -L¹-R¹¹, wherein said aryl and heteroarylmay optionally be substituted by one, two, or three substituentsindependently selected from C₁₋₄ alkyl, halogen, —OR⁹, and —NR^(a)R^(b),and wherein said cycloalkyl and heterocyclyl may optionally besubstituted by one or more, preferably one to three, substituentsindependently selected from C₁₋₄ alkyl, —OR⁹, —NR^(a)R^(b), and oxo;

R⁸ is C₁₋₄ alkyl or benzyl;

R⁹ is hydrogen or C₁₋₄ alkyl;

R¹⁰ is hydrogen, C₁₋₄ alkyl, or benzyl;

L¹ is C₁₋₂ alkylene optionally substituted by one or two substituentsindependently selected from C₁₋₄ alkyl, —OR¹², —OC(O)R¹³, —NR^(a)R^(b),and oxo;

R¹¹ is C₁₋₄ alkyl, cycloalkyl, aryl, or heteroaryl, wherein said aryl orheteroaryl may optionally be substituted by one, two, or threesubstituents independently selected from C₁₋₄ alkyl, halogen, —OR⁹, and—NR^(a)R^(b), and wherein said cycloalkyl or heterocyclyl may optionallybe substituted by one, two, or three substituents independently selectedfrom C₁₋₄ alkyl, halogen, —OR⁹, oxo, and —NR^(a)R^(b);

R¹² is hydrogen or C₁₋₄ alkyl;

R¹³ is C₁₋₄ alkyl;

R^(17b) is —OR⁸; and

R^(a) and R^(b) are each independently hydrogen or C₁₋₄ alkyl.

In an eighth embodiment of the first aspect, the present disclosureprovides a compound of Formula (Ic), or a stereoisomer or apharmaceutically acceptable salt or solvate thereof, wherein:

R^(x) is hydrogen;

R⁷ at each occurrence is selected from the group consisting of —OCH₂Ph,—OC(CH₃)₃, —CH₂Ph, cyclopropyl, cyclobutyl,

and

R^(17b) is —OC(CH₃)₃ or —OCH₂Ph.

In a ninth embodiment of the first aspect, the present disclosureprovides a compound of Formula (Id):

or a stereoisomer or a pharmaceutically acceptable salt or solvatethereof, wherein:

R^(x) is hydrogen or C₁₋₄ alkyl;

R¹ and R² are each independently

R¹⁶ is hydrogen or —OH;

R¹⁷ at each occurrence is independently hydrogen or —C(O)R⁷;

R⁷ at each occurrence is independently selected from the groupconsisting of —OR⁸, C₁₋₄ alkyl, heteroaryl, and -L¹-R¹¹, wherein saidheteroaryl may optionally be substituted by one, two, or threesubstituents independently selected from C₁₋₄ alkyl, halogen, and —OR⁹;

R⁸ is C₁₋₄ alkyl or benzyl;

R⁹ is hydrogen or C₁₋₄ alkyl;

L¹ is C₁₋₂ alkylene optionally substituted by one or two substituentsindependently selected from C₁₋₄ alkyl, —OR¹², and oxo;

R¹¹ is aryl, C₁₋₄ alkyl, cycloalkyl, aryl, or heteroaryl, wherein saidaryl or heteroaryl may optionally be substituted by one, two, or threesubstituents independently selected from C₁₋₄ alkyl, halogen, and —OR⁹;and

R¹² is hydrogen or C₁₋₄ alkyl.

In a tenth embodiment of the first aspect, the present disclosureprovides a compound of Formula (Ie):

or a pharmaceutically acceptable salt or solvate thereof, wherein:

R^(x) and R^(y) are each independently hydrogen or C₁₋₄ alkyl;

R¹ and R² are each independently selected from

R¹⁶ is hydrogen or —OR⁴, wherein R⁴ is hydrogen or C₁₋₄ alkyl;

R¹⁷ at each occurrence is independently hydrogen or —C(O)R⁷;

R⁷ at each occurrence is independently selected from the groupconsisting of: —OR⁸, C₁₋₄ alkyl, aryl, C₃₋₆ cycloalkyl, heterocyclyl,heteroaryl, and -L¹-R¹¹, wherein said aryl and heteroaryl may optionallybe substituted by one, two, or three substituents independently selectedfrom C₁₋₄ alkyl, halogen, —OR⁹, and —NR^(a)R^(b), and wherein saidcycloalkyl and heterocyclyl may optionally be substituted by one ormore, preferably one to three, substituents independently selected fromC₁₋₄ alkyl, —OR⁹, —NR^(a)R^(b), and oxo;

R⁸ is C₁₋₄ alkyl or benzyl;

R⁹ is hydrogen or C₁₋₄ alkyl;

L¹ is C₁₋₂ alkylene optionally substituted by one or two substituentsindependently selected from C₁₋₄ alkyl, —OR¹², —OC(O)R¹³, —NR^(a)R^(b),and oxo;

R¹¹ is C₁₋₄ alkyl, cycloalkyl, aryl, or heteroaryl, wherein said aryl orheteroaryl may be optionally substituted by one, two, or threesubstituents independently selected from C₁₋₄ alkyl, halogen, —OR⁹, and—NR^(a)R^(b), and wherein said cycloalkyl or heterocyclyl may optionallybe substituted by one or more, preferably one to three, substituentsindependently selected from C₁₋₄ alkyl, halogen, —OR⁹, oxo, and—NR^(a)R^(b);

R⁹ is hydrogen, C₁₋₄ alkyl, or C₁₋₄ haloalkyl;

R¹⁰ is C₁₋₄ alkyl or benzyl;

R¹² is hydrogen or C₁₋₄ alkyl;

R¹³ is C₁₋₄ alkyl;

R^(a) and R^(b) are each independently hydrogen, C₁₋₄ alkyl, or—C(O)R¹⁴; and

R¹⁴ is C₁₋₄ alkyl.

In an eleventh embodiment of the first aspect, the present disclosureprovides a compound of Formula (Ie), or a stereoisomer or apharmaceutically acceptable salt or solvate thereof, wherein:

R^(x) is hydrogen;

R^(y) is hydrogen or C₁₋₄ alkyl; and

R⁷ at each occurrence is independently selected from the groupconsisting of —OCH₂Ph, —OC(CH₃)₃, methyl, ethyl, isopropyl, benzyl,cyclopropyl, cyclobutyl,

In a twelfth embodiment of the first aspect, the present disclosureprovides a compound of Formula (If):

or a stereoisomer or a pharmaceutically acceptable salt or solvatethereof, wherein:

R^(x) is hydrogen or C₁₋₄ alkyl;

R¹ and R² are each independently

R¹⁶ is hydrogen or —OH;

R¹⁷ at each occurrence is independently hydrogen or —C(O)R⁷;

R⁷ at each occurrence is independently —OR⁸ or —CH₂Ph; and

R⁸ is C₁₋₄ alkyl or benzyl.

In a thirteenth embodiment of the first aspect, the present disclosureprovides a compound of Formula (Ig):

or a stereoisomer or a pharmaceutically acceptable salt or solvatethereof, wherein:

R^(y) is hydrogen or C₁₋₄ alkyl;

R¹ and R² are each independently

R¹⁷ at each occurrence is independently hydrogen or —C(O)R⁷; and

R⁷ at each occurrence is independently —OR⁸; and

R⁸ is C₁₋₄ alkyl or benzyl.

In a fourteenth embodiment of the first aspect, the present disclosureprovides a compound of Formula (Ih):

or a stereoisomer or a pharmaceutically acceptable salt or solvatethereof, wherein:

R^(y) is hydrogen or C₁₋₄ alkyl;

R¹ and R² are each independently

R¹⁶ is hydrogen or —OH; and

R¹⁷ at each occurrence is independently hydrogen or —C(O)R⁷;

R⁷ at each occurrence is independently —OR⁸ or benzyl; and

R⁸ is C₁₋₄ alkyl or benzyl.

In a fifteenth embodiment of the first aspect, the present disclosureprovides a compound of Formula (Ii):

or a stereoisomer or a pharmaceutically acceptable salt or solvatethereof, wherein:

Q is S or O;

R¹ and R² are each independently

R¹⁷ at each occurrence is independently hydrogen or —C(O)R⁷; and

R⁷ at each occurrence is independently selected from the groupconsisting of —OR⁸, C₁₋₄ alkyl, and benzyl; and

R⁸ is C₁₋₄ alkyl or benzyl.

In a sixteenth embodiment of the first aspect, the present disclosureprovides a compound of Formula (Ij):

or a stereoisomer or a pharmaceutically acceptable salt or solvatethereof, wherein:

R^(x) is hydrogen or C₁₋₄ alkyl;

R¹ and R² are each independently

R¹⁷ at each occurrence is independently hydrogen or —C(O)R⁷; and

R⁷ at each occurrence is independently C₁₋₄ alkyl or benzyl.

In a seventeenth embodiment of the first aspect, the present disclosureprovides a compound of Formula (Ik):

or a stereoisomer or a pharmaceutically acceptable salt or solvatethereof, wherein:

R^(x) is hydrogen or C₁₋₄ alkyl;

R¹ and R² are independently selected from:

R¹⁷ at each occurrence is independently hydrogen or —C(O)R⁷;

R⁷ at each occurrence is independently C₁₋₄ alkyl, phenyl, C₁₋₆ alkoxy,thienyl, isoxazolyl, tetrahydrofuryl, or benzyl; and

R^(17a) is

In a second aspect the present disclosure provides a compositioncomprising a compound of Formula (I):

or a pharmaceutically acceptable salt or solvate thereof, and apharmaceutically acceptable carrier, wherein Formula (I) is definedaccording to any of the embodiments described above in the first aspectof the present disclosure.

In a first embodiment of the second aspect the composition furthercomprises at least one additional compound having anti-HCV activity.

In a second embodiment of the second aspect at least one of theadditional compounds is an interferon or a ribavirin.

In a third embodiment of the second aspect the interferon is selectedfrom interferon alpha 2B, pegylated interferon alpha, consensusinterferon, interferon alpha 2A, and lymphoblastiod interferon tau.

In a fourth embodiment of the second aspect the present disclosureprovides a composition comprising a compound of Formula (I), or apharmaceutically acceptable salt or solvate thereof, a pharmaceuticallyacceptable carrier, and at least one additional compound having anti-HCVactivity, wherein at least one of the additional compounds is selectedfrom interleukin 2, interleukin 6, interleukin 12, a compound thatenhances the development of a type 1 helper T cell response, interferingRNA, anti-sense RNA, Imiqimod, ribavirin, an inosine 5′-monophospatedehydrogenase inhibitor, amantadine, and rimantadine.

In a fifth embodiment of the second aspect the present disclosureprovides a composition comprising a compound of Formula (I), or apharmaceutically acceptable salt or solvate thereof, a pharmaceuticallyacceptable carrier, and at least one additional compound having anti-HCVactivity, wherein at least one of the additional compounds is effectiveto inhibit the function of a target selected from HCV metalloprotease,HCV serine protease, HCV polymerase, HCV helicase, HCV NS4B protein, HCVentry, HCV assembly, HCV egress, HCV NS5A protein, and IMPDH for thetreatment of an HCV infection.

In a third aspect the present disclosure provides a method of treatingan HCV infection in a patient, comprising administering to the patient atherapeutically effective amount of a compound of Formula (I):

or a pharmaceutically acceptable salt or solvate thereof, whereinFormula (I) is defined according to any of the embodiments describedabove in the first aspect of the present disclosure.

In a first embodiment of the third aspect the method further comprisesadministering at least one additional compound having anti-HCV activityprior to, after or simultaneously with the compound of Formula (I), or apharmaceutically acceptable salt or solvate thereof.

In a second embodiment of the third aspect at least one of theadditional compounds is an interferon or a ribavirin.

In a third embodiment of the third aspect the interferon is selectedfrom interferon alpha 2B, pegylated interferon alpha, consensusinterferon, interferon alpha 2A, and lymphoblastiod interferon tau.

In a fourth embodiment of the third aspect the present disclosureprovides a method of treating an HCV infection in a patient, comprisingadministering to the patient a therapeutically effective amount of acompound of Formula (I), or a pharmaceutically acceptable salt orsolvate thereof, and at least one additional compound having anti-HCVactivity prior to, after or simultaneously with the compound of Formula(I), or a pharmaceutically acceptable salt or solvate thereof, whereinat least one of the additional compounds is selected from interleukin 2,interleukin 6, interleukin 12, a compound that enhances the developmentof a type 1 helper T cell response, interfering RNA, anti-sense RNA,Imiqimod, ribavirin, an inosine 5′-monophospate dehydrogenase inhibitor,amantadine, and rimantadine.

In a fifth embodiment of the third aspect the present disclosureprovides a method of treating an HCV infection in a patient, comprisingadministering to the patient a therapeutically effective amount of acompound of Formula (I), or a pharmaceutically acceptable salt orsolvate thereof, and at least one additional compound having anti-HCVactivity prior to, after or simultaneously with the compound of Formula(I), or a pharmaceutically acceptable salt or solvate thereof, whereinat least one of the additional compounds is effective to inhibit thefunction of a target selected from HCV metalloprotease, HCV serineprotease, HCV polymerase, HCV helicase, HCV NS4B protein, HCV entry, HCVassembly, HCV egress, HCV NS5A protein, and IMPDH for the treatment ofan HCV infection.

In another aspect the present disclosure provides a compound of Formula(X):

or a stereoisomer or a pharmaceutically acceptable salt or solvatethereof, wherein:

L is a five-membered heterocyclyl group selected from the groupconsisting of

wherein R^(x) at each occurrence is independently hydrogen, halogen, orC₁₋₄ alkyl optionally substituted by —C(O)OR³ or —NMe₂, wherein R^(y) ateach occurrence is independently hydrogen or C₁₋₄ alkyl, and wherein R³is hydrogen or C₁₋₄ alkyl;

R¹ and R² are independently selected from cycloalkyl, heteroaryl,heterocyclyl, C₁₋₆ alkoxy, —NHR^(p), and alkyl, wherein said alkyl isoptionally substituted by one, two, or three substituents independentlyselected from aryl, alkenyl, cycloalkyl, heterocyclyl, heteroaryl,—OSi(R^(q))₃, —OR⁴, —SR⁵, —C(O)OR⁶, —NHC(O)R⁷, —NR^(a)R^(b), and—C(O)NR^(c)R^(d),

wherein R^(p) is heterocyclyl,

wherein R^(q) at each occurrence is independently C₁₋₄ alkyl or phenyl,

wherein any said aryl or heteroaryl may optionally be substituted withone or more, preferably one to three, substituents independentlyselected from C₁₋₄ alkyl, C₁₋₄ haloalkyl, arylalkyl, heterocyclyl,heterocyclylalkyl, halogen, cyano, nitro, —OR⁴, —C(O)OR⁶, —NR^(a)R^(b),(NR^(a)R^(b))alkyl, and —OP(O)(OH)(OR⁵), and

wherein any said cycloalkyl or heterocyclyl may optionally be fused ontoan aromatic ring and may optionally be substituted with one or more,preferably one to three, substituents independently selected from C₁₋₄alkyl, halogen, aryl, arylalkyl, heteroarylalkyl, fused cyclopropyl,—NR^(a)R^(b), oxo, —OR⁴, —C(O)OR⁶, and —C(O)R⁷;

R⁴ is hydrogen, C₁₋₆ alkyl, or benzyl;

R⁵ is hydrogen or C₁₋₄ alkyl;

R⁶ at each occurrence is independently C₁₋₆ alkyl, aryl, benzyl, orheteroaryl;

R⁷ at each occurrence is independently selected from —OR⁸, C₁₋₆ alkyl,C₁₋₆ haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and -L¹-R¹¹,wherein said aryl and heteroaryl may optionally be substituted by one ormore, preferably one to three, substituents independently selected fromC₁₋₄ alkyl, halogen, —OR⁹, and —NR^(a)R^(b), and wherein said cycloalkyland heterocyclyl may optionally be substituted by one or more,preferably one to three, substituents independently selected from C₁₋₄alkyl, —C(O)OR¹⁰, oxo, phenyl, fused cyclopropyl, —NR^(a)R^(b), -L¹-R¹¹,—C(O)R¹¹, and —C(O)—L¹-R¹¹;

R⁸ is C₁₋₆ alkyl or arylalkyl;

R⁹ is hydrogen, C₁₋₆ alkyl, or C₁₋₄ haloalkyl;

R¹⁰ is hydrogen, C₁₋₆ alkyl, phenyl, or benzyl;

L¹ is C₁₋₂ alkylene optionally substituted by one or two substituentsindependently selected from C₁₋₄ alkyl, —OR¹², —OC(O)R¹³, —NR^(a)R^(b),phenyl, and oxo;

R¹¹ is C₁₋₆ alkyl, C₁₋₄ haloalkyl, cycloalkyl, heterocyclyl, aryl,heteroaryl, or —NR^(a)R^(b), wherein said aryl or heteroaryl mayoptionally be substituted by one or more, preferably one to three,substituents independently selected from C₁₋₄ alkyl, halogen, —OR⁹,nitro, cyano, and —NR^(a)R^(b), and wherein said cycloalkyl orheterocyclyl may optionally be substituted by one or more, preferablyone to three, substituents independently selected from C₁₋₄ alkyl,benzyl, phenyl, halogen, —OR⁹, oxo, fused cyclopropyl, —NR^(a)R^(b),—C(O)R¹⁰, and —C(O)OR¹⁰;

R¹² is hydrogen, C₁₋₄ alkyl, aryl, or heteroaryl, wherein said aryl orheteroaryl may optionally be substituted by one or more, preferably oneto three, substituents independently selected from C₁₋₄ alkyl, halogen,and —OR⁹;

R¹³ is C₁₋₄ alkyl or aryl;

R^(a) and R^(b) are independently selected from hydrogen, C₁₋₆ alkyl,cycloalkyl, arylalkyl, heteroaryl, heterocyclyl, —C(O)R¹⁴, —C(O)OR¹⁵,—C(O)NR^(c)R^(d), and (NR^(c)R^(d))alkyl, or alternatively, R^(a) andR^(b), together with the nitrogen atom to which they are attached, forma five- or six-membered ring or bridged bicyclic ring structure, whereinsaid five- or six-membered ring or bridged bicyclic ring structureoptionally may contain one or two additional heteroatoms independentlyselected from nitrogen, oxygen, and sulfur and may contain one, two, orthree substituents independently selected from C₁₋₆ alkyl, C₁₋₄haloalkyl, aryl, halogen, and —OR⁹;

R^(c) and R^(d) are independently selected from hydrogen, C₁₋₄ alkyl,benzyl, and cycloalkyl;

R¹⁴ is C₁₋₄ alkyl, arylalkyl, aryl, or heteroaryl, each optionallysubstituted by one, two or three substituents independently selectedfrom C₁₋₄ alkyl, halogen, and —OR⁹; and

R¹⁵ is C₁₋₆ alkyl, arylalkyl, or C₁₋₄ haloalkyl.

Other aspects of the present disclosure may include suitablecombinations of embodiments disclosed herein.

Yet other aspects and embodiments may be found in the descriptionprovided herein.

The description of the present disclosure herein should be construed incongruity with the laws and principals of chemical bonding. In someinstances it may be necessary to remove a hydrogen atom in order toaccommodate a substituent at any given location.

Certain features of the structure of Formula (I) are further illustratedbelow:

In Formula (I), R¹ and R² are independent from each other, although insome circumstances they are preferably the same.

R¹C(O)— and R²C(O)— can be derived from any of the “Caps” disclosedherein, and in principle can be derived from any carboxylic acid orderivatives. When R¹ or R² contains a nitrogen that can be “capped” withan acyl group, for example, when R¹ or R² is an amino alkyl group or anitrogen-containing heterocyclyl group, such an acyl group can also bederived from any of the “Caps” disclosed herein.

When a “cap” contains a stereogenic center, the stereogeneic center cantake either (R)- or (S)-configuration. For example, apyrrolidine-containing “cap” can take either (R)- or (S)-configurationas depicted below:

When a cyclopropyl ring is fused onto a cycloalkyl or heterocyclyl ring,the CH₂ group of the fused cyclopropyl ring can take either α- orβ-position. For example, a pyrrolidine ring with a fused cyclopropylgroup may take either of the two forms depicted below:

Thus, this disclosure is intended to cover all possible stereoisomerseven when a single stereoisomer, or no stereochemistry, is described ina structure. It should be understood that the compounds encompassed bythe present disclosure are those that are suitably stable for use aspharmaceutical agent.

It is intended that the definition of any substituent or variable at aparticular location in a molecule be independent of its definitionselsewhere in that molecule. For example, for substituent (R¹⁶)_(n), whenn is 2, each of the two R¹⁶ groups may be the same or different.

All patents, patent applications, and literature references cited in thespecification are herein incorporated by reference in their entirety. Inthe case of inconsistencies, the present disclosure, includingdefinitions, will prevail.

DEFINITIONS

Definitions have been provided above for each of the groups defined. Inaddition, the following definitions shall be used.

As used herein, the singular forms “a”, “an”, and “the” include pluralreference unless the context clearly dictates otherwise.

Unless stated otherwise, all aryl, cycloalkyl, heteroaryl, andheterocyclyl groups of the present disclosure may be substituted asdescribed in each of their respective definitions. For example, the arylpart of an arylalkyl group may be substituted as described in thedefinition of the term “aryl.”The term “acetyl,” as used herein, refersto —C(O)CH₃.

The term “alkenyl,” as used herein, refers to a monovalent, straight orbranched hydrocarbon chain having one or more, preferably one to two,double bonds therein. The double bond of an alkenyl group can beunconjugated or conjugated to another unsaturated group. Suitablealkenyl groups include, but are not limited to, C₂ to C₁₀ alkenylgroups, such as vinyl, allyl, butenyl, pentenyl, hexenyl, butadienyl,pentadienyl, hexadienyl, 2-ethylhexenyl, 2-propyl-2-butenyl,4-(2-methyl-3-butene)-pentenyl. An alkenyl group can be unsubstituted orsubstituted with one or two suitable substituents.

The term “alkoxy,” as used herein, refers to an alkyl group attached tothe parent molecular moiety through an oxygen atom. Representativeexamples of alkoxy group include, but are not limited to, methoxy(CH₃O—), ethoxy (CH₃CH₂O—), and t-butoxy ((CH₃)₃CO—).

The term “alkyl,” as used herein, refers to a group derived from astraight or branched chain saturated hydrocarbon by removal of ahydrogen from one of the saturated carbons. The alkyl group preferablycontains from one to ten carbon atoms. Representative examples of alkylgroup include, but are not limited to, methyl, ethyl, isopropyl, andtert-butyl.

The term “alkylcarbonyl,” as used herein, refers to an alkyl groupattached to the parent molecular moiety through a carbonyl group.Representative examples of alkylcarbonyl group include, but are notlimited to, acetyl (—C(O)CH₃), propanoyl (—C(O)CH₂CH₃), n-butyryl(—C(O)CH₂CH₂CH₃), and 2,2-dimethylpropanoyl or pivaloyl (—C(O)C(CH₃)₃).

The term “allyl,” as used herein, refers to the —CH₂CH═CH₂ group.

The term “aryl,” as used herein, refers to a group derived from anaromatic carbocycle by removal of a hydrogen atom from an aromatic ring.The aryl group can be monocyclic, bicyclic or polycyclic, wherein inbicyclic or polycyclic aryl group, the aromatic carbocycle can be fusedonto another four- to six-membered aromatic or non-aromatic carbocycle.Representative examples of aryl groups include, but are not limited to,phenyl, indanyl, indenyl, naphthyl, and 1,2,3,4-tetrahydronaphth-5-yl.

The term “arylalkyl,” as used herein, refers to an alkyl groupsubstituted with one, two, or three aryl groups, wherein aryl part ofthe arylalkyl group may optionally be substituted by one to fivesubstituents independently selected from C₁ to C₆ alkyl, C₁ to C₄haloalkyl, C₁ to C₆ alkoxy, halogen, cyano, and nitro groups.Represented examples of arylalkyl include, but are not limited to,benzyl, 2-phenyl-1-ethyl (PhCH₂CH₂—), (naphth-1-yl)methyl, and(naphth-2-yl)methyl.

The term “benzyl,” as used herein, refers to a methyl group on which oneof the hydrogen atoms is replaced by a phenyl group, wherein said phenylgroup may optionally be substituted by one to five substituentsindependently selected from methyl, trifluoromethyl (—CF₃), methoxy(—OCH₃), halogen, and nitro (—NO₂). Representative examples of benzylgroup include, but are not limited to, PhCH₂—, 4-MeO—C₆H₄—CH₂—, and2,4,6-tri-methyl-C₆H₄—CH₂—.

The term “bridged bicyclic ring,” as used herein, refers to a ringstructure comprising a bridgehead between two of the ring members,wherein the ring and the bridgehead optionally may independentlycomprise one or more, preferably one to two, heteroatoms independentlyselected from nitrogen, oxygen, and sulfur. Illustrated examples of abridged bicyclic ring structure include, but are not limited to:

The terms “Cap” and “cap,” as used herein, refer to a group that can beused to replace the R¹C(O)— or R²C(O)— group in formula (I) or an acylgroup residing at a nitrogen atom in the R¹ or R² group, for example,the R⁷C(O)— group. It should be understood that “Cap” or “cap” can alsorefer to a reagent which is a precursor to the final “cap” in a compoundof formula (I), for example, a carboxylic acid or its derivatives thatcan react with an amino group to form an amide bond, such as an ester,acyl halide, acyl azide, and so on.

The term “carbonyl,” as used herein, refers to —C(O)—.

The term “carboxyl,” as used herein, refers to —CO₂H.

The term “cyano,” as used herein, refers to —CN.

The term “cycloalkyl,” as used herein, refers to a group derived from asaturated carbocycle, having preferably three to eight carbon atoms, byremoval of a hydrogen atom from the saturated carbocycle, wherein thesaturated carbocyle can optionally be fused onto one or two otheraromatic or nonaromatic carbocycles. Representative examples ofcycloalkyl groups include, but are not limited to, cyclopropyl,cyclopentyl, cyclohexyl, and 1,2,3,4-tetrahydronaphth-1-yl.

The term “formyl,” as used herein, refers to —CHO.

The term “fused cyclopropyl,” as used herein, refers to a cyclopropylring fused onto another ring structure, i.e., a methylene group (—CH₂—)attached to two adjacent carbon atoms, as illustrated in the group:

The terms “halo” and “halogen,” as used herein, refer to F, Cl, Br, orI.

The term “haloalkoxy,” as used herein, refers to a haloalkyl groupattached to the parent molecular moiety through an oxygen atom.

The term “haloalkyl,” as used herein, refers to an alkyl groupsubstituted by at least one halogen atom. The haloalkyl group can be analkyl group of which all hydrogen atoms are substituted by halogens.Representative examples of haloalkyl include, but are not limited to,trifluoromethyl (CF₃—), 1-chloroethyl (ClCH₂CH₂—), and2,2,2-trifluoroethyl (CF₃CH₂—).

The term “heteroaryl,” as used herein, refers to group derived from amonocyclic, bicyclic, or polycyclic compound comprising at least onearomatic ring comprising one or more, preferably one to three,heteroatoms independently selected from nitrogen, oxygen, and sulfur, byremoval of a hydrogen atom from an aromatic ring thereof. As is wellknown to those skilled in the art, heteroaryl rings have less aromaticcharacter than their all-carbon counterparts. Thus, for the purposes ofthe disclosure, a heteroaryl group need only have some degree ofaromatic character. Illustrative examples of heteroaryl groups include,but are not limited to, pyridyl, pyridazinyl, pyrimidyl, pyrazyl,triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3,)- and(1,2,4)-triazolyl, pyrazinyl, pyrimidinyl, tetrazolyl, furyl, thienyl,isoxazolyl, thiazolyl, isoxazolyl, oxazolyl, indolyl, quinolinyl,isoquinolinyl, benzisoxazolyl, benzothiazolyl, benzothienyl, andpyrrolopyridinyl.

The term “heteroarylalkyl,” as used herein, refers to an alkyl groupsubstituted with one, two, or three heteroaryl groups.

The term “heterobicyclyl,” as used herein, refers to a ring structurecomprising two fused, bridged, or spirocyclic rings that include carbonand one or more, preferably one to three, heteroatoms independentlyselected from nitrogen, oxygen, and sulfur. The heterobicyclic ringstructure is a subset of heterocyclic ring and can be saturated orunsaturated. Examples of heterobicyclic ring structures include, but arenot limited to, tropane, quinuclidine, and 7-azabicyclo[2.2.1]heptane.

The term “heterocyclyl,” as used herein, refers to a group derived froma monocyclic, bicyclic, or polycyclic compound comprising at least onenonaromatic ring comprising one or more, preferably one to three,heteroatoms independently selected from nitrogen, oxygen, and sulfur, byremoval of a hydrogen atom from the nonaromatic ring. The heterocyclylgroup encompasses the heterobicyclyl group. The heterocyclyl groups ofthe present disclosure can be attached to the parent molecular moietythrough a carbon atom or a nitrogen atom in the group. Examples ofheterocyclyl groups include, but are not limited to, morpholinyl,oxazolidinyl, piperazinyl, piperidinyl, pyrrolidinyl, tetrahydrofuryl,thiomorpholinyl, and indolinyl.

The term “heterocyclylalkyl,” as used herein, refers to an alkyl groupsubstituted with one, two, or three heterocyclyl groups.

The terms “hydroxy” or “hydroxyl,” as used herein, refer to —OH.

The term “nitro,” as used herein, refers to —NO₂.

The term “—NR^(a)R^(b),” as used herein, refers to two groups, R^(a) andR^(b), which are attached to the parent molecular moiety through anitrogen atom, or alternatively R^(a) and R^(b), together with thenitrogen atom to which they are attached, form a 5- or 6-membered ringor a fused- or bridged-bicyclic ring structure optionally containingone, two, or three additional heteroatom independently selected fromnitrogen, oxygen, and sulfur. The term “—NR^(c)R^(d)” is definedsimilarly.

The term “(NR^(a)R^(b))alkyl,” as used herein, refers to an alkyl groupsubstituted with one, two, or three —NR^(a)R^(b) groups. The term“(NR^(c)R^(d))alkyl” is defined similarly.

The term “oxo,” as used herein, refers to ═O.

The term “sulfonyl,” as used herein, refers to —SO₂—.

The term “trialkylsilyl,” as used herein, refers to —SiR₃, wherein eachR is C₁ to C₄ alkyl or phenyl. The three R groups may be the same ordifferent. Representative examples of “trialkylsilyl” include, but arenot limited to, trimethylsilyl (TMS), tert-butyldiphenylsilyl (TBDPS),tert-butyldimethylsilyl (TBS or TBDMS), and triisopropylsilyl (TIPS).

Asymmetric centers exist in the compounds of the present disclosure.These centers are designated by the symbols “R” or “S”, depending on theconfiguration of substituents around the chiral carbon atom. It shouldbe understood that the disclosure encompasses all stereochemicalisomeric forms, or mixtures thereof, which possess the ability toinhibit NS5A. Individual stereoisomers of compounds can be preparedsynthetically from commercially available starting materials whichcontain chiral centers or by preparation of mixtures of enantiomericproducts followed by separation such as conversion to a mixture ofdiastereomers followed by separation or recrystallization,chromatographic techniques, or direct separation of enantiomers onchiral chromatographic columns. Starting compounds of particularstereochemistry are either commercially available or can be made andresolved by techniques known in the art.

Certain compounds of the present disclosure may also exist in differentstable conformational forms which may be separable. Torsional asymmetrydue to restricted rotation about an asymmetric single bond, for examplebecause of steric hindrance or ring strain, may permit separation ofdifferent conformers. The present disclosure includes eachconformational isomer of these compounds and mixtures thereof.

The term “compounds of the present disclosure”, and equivalentexpressions, are meant to embrace compounds of Formula (I), andpharmaceutically acceptable enantiomers, diastereomers, and saltsthereof. Similarly, references to intermediates are meant to embracetheir salts where the context so permits.

The present disclosure is intended to include all isotopes of atomsoccurring in the present compounds. Isotopes include those atoms havingthe same atomic number but different mass numbers. By way of generalexample and without limitation, isotopes of hydrogen include deuteriumand tritium. Isotopes of carbon include ¹³C and ¹⁴C.Isotopically-labeled compounds of the invention can generally beprepared by conventional techniques known to those skilled in the art orby processes analogous to those described herein, using an appropriateisotopically-labeled reagent in place of the non-labeled reagentotherwise employed. Such compounds may have a variety of potential uses,for example as standards and reagents in determining biologicalactivity. In the case of stable isotopes, such compounds may have thepotential to favorably modify biological, pharmacological, orpharmacokinetic properties.

The compounds of the present disclosure can exist as pharmaceuticallyacceptable salts or solvates. The term “pharmaceutically acceptablesalt,” as used herein, represents salts or zwitterionic forms of thecompounds of the present disclosure which are water or oil-soluble ordispersible, which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of patients withoutexcessive toxicity, irritation, allergic response, or other problem orcomplication commensurate with a reasonable benefit/risk ratio, and areeffective for their intended use The salts can be prepared during thefinal isolation and purification of the compounds or separately byreacting a suitable nitrogen atom with a suitable acid. Representativeacid addition salts include acetate, adipate, alginate, citrate,aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate,camphorsulfonate; digluconate, glycerophosphate, hemisulfate,heptanoate, hexanoate, formate, fumarate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,mesitylenesulfonate, methanesulfonate, naphthylenesulfonate, nicotinate,2-naphthalenesulfonate, oxalate, palmoate, pectinate, persulfate,3-phenylproprionate, picrate, pivalate, propionate, succinate, tartrate,trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate,para-toluenesulfonate, and undecanoate. Examples of acids which can beemployed to form pharmaceutically acceptable addition salts includeinorganic acids such as hydrochloric, hydrobromic, sulfuric, andphosphoric, and organic acids such as oxalic, maleic, succinic, andcitric.

Basic addition salts can be prepared during the final isolation andpurification of the compounds by reacting a carboxy group with asuitable base such as the hydroxide, carbonate, or bicarbonate of ametal cation or with ammonia or an organic primary, secondary, ortertiary amine. The cations of pharmaceutically acceptable salts includelithium, sodium, potassium, calcium, magnesium, and aluminum, as well asnontoxic quaternary amine cations such as ammonium, tetramethylammonium,tetraethylammonium, methylamine, dimethylamine, trimethylamine,triethylamine, diethylamine, ethylamine, tributylamine, pyridine,N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine,dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine,and N,N′-dibenzylethylenediamine. Other representative organic aminesuseful for the formation of base addition salts include ethylenediamine,ethanolamine, diethanolamine, piperidine, and piperazine.

When it is possible that, for use in therapy, therapeutically effectiveamounts of a compound of Formula (I), as well as pharmaceuticallyacceptable salts or solvates thereof, may be administered as the rawchemical, it is possible to present the active ingredient as apharmaceutical composition. Accordingly, the disclosure further providespharmaceutical compositions, which include therapeutically effectiveamounts of compounds of Formula (I) or pharmaceutically acceptable saltsor solvates thereof, and one or more, preferably one to three,pharmaceutically acceptable carriers, diluents, or excipients. The term“therapeutically effective amount,” as used herein, refers to the totalamount of each active component that is sufficient to show a meaningfulpatient benefit, e.g., a sustained reduction in viral load. When appliedto an individual active ingredient, administered alone, the term refersto that ingredient alone. When applied to a combination, the term refersto combined amounts of the active ingredients that result in thetherapeutic effect, whether administered in combination, serially, orsimultaneously. The compounds of Formula (I) and pharmaceuticallyacceptable salts or solvates thereof, are as described above. Thecarrier(s), diluent(s), or excipient(s) must be acceptable in the senseof being compatible with the other ingredients of the formulation andnot deleterious to the recipient thereof. In accordance with anotheraspect of the present disclosure there is also provided a process forthe preparation of a pharmaceutical formulation including admixing acompound of Formula (I), or a pharmaceutically acceptable salt orsolvate thereof, with one or more, preferably one to three,pharmaceutically acceptable carriers, diluents, or excipients. The term“pharmaceutically acceptable,” as used herein, refers to thosecompounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of patients without excessive toxicity, irritation,allergic response, or other problem or complication commensurate with areasonable benefit/risk ratio, and are effective for their intended use.

Pharmaceutical formulations may be presented in unit dose formscontaining a predetermined amount of active ingredient per unit dose.Dosage levels of between about 0.01 and about 250 milligram per kilogram(“mg/kg”) body weight per day, preferably between about 0.05 and about100 mg/kg body weight per day of the compounds of the present disclosureare typical in a monotherapy for the prevention and treatment of HCVmediated disease. Typically, the pharmaceutical compositions of thisdisclosure will be administered from about 1 to about 5 times per day oralternatively, as a continuous infusion. Such administration can be usedas a chronic or acute therapy. The amount of active ingredient that maybe combined with the carrier materials to produce a single dosage formwill vary depending on the condition being treated, the severity of thecondition, the time of administration, the route of administration, therate of excretion of the compound employed, the duration of treatment,and the age, gender, weight, and condition of the patient. Preferredunit dosage formulations are those containing a daily dose or sub-dose,as herein above recited, or an appropriate fraction thereof, of anactive ingredient. Generally, treatment is initiated with small dosagessubstantially less than the optimum dose of the compound. Thereafter,the dosage is increased by small increments until the optimum effectunder the circumstances is reached. In general, the compound is mostdesirably administered at a concentration level that will generallyafford antivirally effective results without causing any harmful ordeleterious side effects.

When the compositions of this disclosure comprise a combination of acompound of the present disclosure and one or more, preferably one ortwo, additional therapeutic or prophylactic agent, both the compound andthe additional agent are usually present at dosage levels of betweenabout 10 to 150%, and more preferably between about 10 and 80% of thedosage normally administered in a monotherapy regimen.

Pharmaceutical formulations may be adapted for administration by anyappropriate route, for example by the oral (including buccal orsublingual), rectal, nasal, topical (including buccal, sublingual, ortransdermal), vaginal, or parenteral (including subcutaneous,intracutaneous, intramuscular, intra-articular, intrasynovial,intrasternal, intrathecal, intralesional, intravenous, or intradermalinjections or infusions) route. Such formulations may be prepared by anymethod known in the art of pharmacy, for example by bringing intoassociation the active ingredient with the carrier(s) or excipient(s).Oral administration or administration by injection are preferred.

Pharmaceutical formulations adapted for oral administration may bepresented as discrete units such as capsules or tablets; powders orgranules; solutions or suspensions in aqueous or non-aqueous liquids;edible foams or whips; or oil-in-water liquid emulsions or water-in-oilemulsions.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic pharmaceutically acceptable inert carrier such as ethanol,glycerol, water, and the like. Powders are prepared by comminuting thecompound to a suitable fine size and mixing with a similarly comminutedpharmaceutical carrier such as an edible carbohydrate, as, for example,starch or mannitol. Flavoring, preservative, dispersing, and coloringagent can also be present.

Capsules are made by preparing a powder mixture, as described above, andfilling formed gelatin sheaths. Glidants and lubricants such ascolloidal silica, talc, magnesium stearate, calcium stearate, or solidpolyethylene glycol can be added to the powder mixture before thefilling operation. A disintegrating or solubilizing agent such asagar-agar, calcium carbonate, or sodium carbonate can also be added toimprove the availability of the medicament when the capsule is ingested.

Moreover, when desired or necessary, suitable binders, lubricants,disintegrating agents, and coloring agents can also be incorporated intothe mixture. Suitable binders include starch, gelatin, natural sugarssuch as glucose or beta-lactose, corn sweeteners, natural and syntheticgums such as acacia, tragacanth or sodium alginate,carboxymethylcellulose, polyethylene glycol, and the like. Lubricantsused in these dosage forms include sodium oleate, sodium chloride, andthe like. Disintegrators include, without limitation, starch, methylcellulose, agar, betonite, xanthan gum, and the like. Tablets areformulated, for example, by preparing a powder mixture, granulating orslugging, adding a lubricant and disintegrant, and pressing intotablets. A powder mixture is prepared by mixing the compound, suitablecomminuted, with a diluent or base as described above, and optionally,with a binder such as carboxymethylcellulose, an aliginate, gelating, orpolyvinyl pyrrolidone, a solution retardant such as paraffin, aresorption accelerator such as a quaternary salt and/or and absorptionagent such as betonite, kaolin, or dicalcium phosphate. The powdermixture can be granulated by wetting with a binder such as syrup, starchpaste, acadia mucilage, or solutions of cellulosic or polymericmaterials and forcing through a screen. As an alternative togranulating, the powder mixture can be run through the tablet machineand the result is imperfectly formed slugs broken into granules. Thegranules can be lubricated to prevent sticking to the tablet formingdies by means of the addition of stearic acid, a stearate salt, talc, ormineral oil. The lubricated mixture is then compressed into tablets. Thecompounds of the present disclosure can also be combined with a freeflowing inert carrier and compressed into tablets directly without goingthrough the granulating or slugging steps. A clear or opaque protectivecoating consisting of a sealing coat of shellac, a coating of sugar orpolymeric material, and a polish coating of wax can be provided.Dyestuffs can be added to these coatings to distinguish different unitdosages.

Oral fluids such as solution, syrups, and elixirs can be prepared indosage unit form so that a given quantity contains a predeterminedamount of the compound. Syrups can be prepared by dissolving thecompound in a suitably flavored aqueous solution, while elixirs areprepared through the use of a non-toxic vehicle. Solubilizers andemulsifiers such as ethoxylated isostearyl alcohols and polyoxyethylenesorbitol ethers, preservatives, flavor additive such as peppermint oilor natural sweeteners, or saccharin or other artificial sweeteners, andthe like can also be added.

Where appropriate, dosage unit formulations for oral administration canbe microencapsulated. The formulation can also be prepared to prolong orsustain the release as for example by coating or embedding particulatematerial in polymers, wax, or the like.

The compounds of Formula (I), and pharmaceutically acceptable salts orsolvates thereof, can also be administered in the form of liposomedelivery systems, such as small unilamellar vesicles, large unilamellarvesicles, and multilamellar vesicles. Liposomes can be formed from avariety of phopholipids, such as cholesterol, stearylamine, orphophatidylcholines.

The compounds of Formula (I) and pharmaceutically acceptable salts orsolvates thereof may also be delivered by the use of monoclonalantibodies as individual carriers to which the compound molecules arecoupled. The compounds may also be coupled with soluble polymers astargetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamidephenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysinesubstituted with palitoyl residues. Furthermore, the compounds may becoupled to a class of biodegradable polymers useful in achievingcontrolled release of a drug, for example, polylactic acid, polepsiloncaprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals,polydihydropyrans, polycyanoacrylates, and cross-linked or amphipathicblock copolymers of hydrogels.

Pharmaceutical formulations adapted for transdermal administration maybe presented as discrete patches intended to remain in intimate contactwith the epidermis of the recipient for a prolonged period of time. Forexample, the active ingredient may be delivered from the patch byiontophoresis as generally described in Pharmaceutical Research 1986,3(6), 318.

Pharmaceutical formulations adapted for topical administration may beformulated as ointments, creams, suspensions, lotions, powders,solutions, pastes, gels, sprays, aerosols, or oils.

For treatments of the eye or other external tissues, for example mouthand skin, the formulations are preferably applied as a topical ointmentor cream. When formulated in an ointment, the active ingredient may beemployed with either a paraffinic or a water-miscible ointment base.Alternatively, the active ingredient may be formulated in a cream withan oil-in-water cream base or a water-in oil base.

Pharmaceutical formulations adapted for topical administrations to theeye include eye drops wherein the active ingredient is dissolved orsuspended in a suitable carrier, especially an aqueous solvent.

Pharmaceutical formulations adapted for topical administration in themouth include lozenges, pastilles, and mouth washes.

Pharmaceutical formulations adapted for rectal administration may bepresented as suppositories or as enemas.

Pharmaceutical formulations adapted for nasal administration wherein thecarrier is a solid include a course powder having a particle size forexample in the range 20 to 500 microns which is administered in themanner in which snuff is taken, i.e., by rapid inhalation through thenasal passage from a container of the powder held close up to the nose.Suitable formulations wherein the carrier is a liquid, foradministration as a nasal spray or nasal drops, include aqueous or oilsolutions of the active ingredient.

Pharmaceutical formulations adapted for administration by inhalationinclude fine particle dusts or mists, which may be generated by means ofvarious types of metered, dose pressurized aerosols, nebulizers, orinsufflators.

Pharmaceutical formulations adapted for vaginal administration may bepresented as pessaries, tampons, creams, gels, pastes, foams, or sprayformulations.

Pharmaceutical formulations adapted for parenteral administrationinclude aqueous and non-aqueous sterile injection solutions which maycontain anti-oxidants, buffers, bacteriostats, and soutes which renderthe formulation isotonic with the blood of the intended recipient; andaqueous and non-aqueous sterile suspensions which may include suspendingagents and thickening agents. The formulations may be presented inunit-dose or multi-dose containers, for example sealed ampoules andvials, and may be stored in a freeze-dried (lyophilized) conditionrequiring only the addition of the sterile liquid carrier, for examplewater for injections, immediately prior to use. Extemporaneous injectionsolutions and suspensions may be prepared from sterile powders,granules, and tablets.

It should be understood that in addition to the ingredients particularlymentioned above, the formulations may include other agents conventionalin the art having regard to the type of formulation in question, forexample those suitable for oral administration may include flavoringagents.

The term “patient” includes both human and other mammals.

The term “treating” refers to: (i) preventing a disease, disorder orcondition from occurring in a patient that may be predisposed to thedisease, disorder, and/or condition but has not yet been diagnosed ashaving it; (ii) inhibiting the disease, disorder, or condition, i.e.,arresting its development; and (iii) relieving the disease, disorder, orcondition, i.e., causing regression of the disease, disorder, and/orcondition.

The compounds of the present disclosure can also be administered with acyclosporin, for example, cyclosporin A. Cyclosporin A has been shown tobe active against HCV in clinical trials (Hepatology 2003, 38, 1282;Biochem. Biophys. Res. Commun. 2004, 313, 42; J. Gastroenterol. 2003,38, 567).

Table 1 below lists some illustrative examples of compounds that can beadministered with the compounds of this disclosure. The compounds of thedisclosure can be administered with other anti-HCV activity compounds incombination therapy, either jointly or separately, or by combining thecompounds into a composition.

TABLE 1 Type of Physiological Inhibitor Brand Name Class or TargetSource Company NIM811 Cyclophilin Novartis Debio-025 inhibitorsDebiopharm Zadaxin Immuno- Sciclone modulator Suvus Methylene blueBioenvision Actilon TLR9 agonist Coley (CPG10101) Batabulin (T67)Anticancer β-Tubulin Tularik Inc., South inhibitor San Francisco, CAISIS 14803 Antiviral Antisense ISIS Pharmaceuticals Inc, Carlsbad,CA/Elan Pharmaceuticals Inc., New York, NY Summetrel Antiviral AntiviralEndo Pharmaceuticals Holdings Inc., Chadds Ford, PA GS-9132 AntiviralHCV inhibitor Achillion/Gilead (ACH-806) Pyrazolopy- Antiviral HCVinhibitors Arrow Therapeutics rimidine Ltd. compounds and salts FromWO2005/047288 26 May 2005 Levovirin Antiviral IMPDH Ribapharm Inc.,inhibitor Costa Mesa, CA Merimepodib Antiviral IMPDH Vertex (VX-497)inhibitor Pharmaceuticals Inc., Cambridge, MA XTL-6865 AntiviralMonoclonal XTL (XTL-002) antibody Biopharmaceuticals Ltd., Rehovot,Israel Telaprevir Antiviral NS3 serine Vertex (VX-950, proteasePharmaceuticals LY-570310) inhibitor Inc., Cambridge, MA/Eli Lilly andCo. Inc., Indianapolis, IN HCV-796 Antiviral NS5B replicaseWyeth/Viropharma inhibitor NM-283 Antiviral NS5B replicaseIdenix/Novartis inhibitor GL-59728 Antiviral NS5B replicase GeneLabs/Novartis inhibitor GL-60667 Antiviral NS5B replicase GeneLabs/Novartis inhibitor 2′C MeA Antiviral NS5B replicase Gileadinhibitor PSI 6130 Antiviral NS5B replicase Roche inhibitor R1626Antiviral NS5B replicase Roche inhibitor 2′C Methyl Antiviral NS5Breplicase Merck adenosine inhibitor JTK-003 Antiviral RdRp inhibitorJapan Tobacco Inc., Tokyo, Japan Levovirin Antiviral Ribavirin ICNPharmaceuticals, Costa Mesa, CA Ribavirin Antiviral RibavirinSchering-Plough Corporation, Kenilworth, NJ Viramidine AntiviralRibavirin Ribapharm Inc., prodrug Costa Mesa, CA Heptazyme AntiviralRibozyme Ribozyme Pharmaceuticals Inc., Boulder, CO BILN-2061 AntiviralSerine protease Boehringer inhibitor Ingelheim Pharma KG, Ingelheim,Germany SCH 503034 Antiviral Serine protease Schering Plough inhibitorZadazim Immune Immune SciClone modulator modulator Pharmaceuticals Inc.,San Mateo, CA Ceplene Immuno- Immune Maxim modulator modulatorPharmaceuticals Inc., San Diego, CA CellCept Immuno- HCV IgG F.Hoffmann-La suppressant immuno- Roche LTD, Basel, suppressantSwitzerland Civacir Immuno- HCV IgG Nabi suppressant immuno-Biopharmaceuticals suppressant Inc., Boca Raton, FL Albuferon-αInterferon Albumin Human Genome IFN-α2b Sciences Inc., Rockville, MDInfergen A Interferon IFN alfacon-1 InterMune Pharmaceuticals Inc.,Brisbane, CA Omega IFN Interferon IFN-ω Intarcia Therapeutics IFN-β andInterferon IFN-β and Transition EMZ701 EMZ701 Therapeutics Inc.,Ontario, Canada Rebif Interferon IFN-β1a Serono, Geneva, SwitzerlandRoferon A Interferon IFN-α2a F. Hoffmann-La Roche LTD, Basel,Switzerland Intron A Interferon IFN-α2b Schering-Plough Corporation,Kenilworth, NJ Intron A and Interferon IFN-α2b/αl- RegeneRx Zadaxinthymosin Biopharma. Inc., Bethesda, MD/ SciClone Pharmaceuticals Inc,San Mateo, CA Rebetron Interferon IFN-α2b/ Schering-Plough ribavirinCorporation, Kenilworth, NJ Actimmune Interferon INF-γ InterMune Inc.,Brisbane, CA Interferon-β Interferon Interferon-β-1a Serono MultiferonInterferon Long lasting IFN Viragen/Valentis Wellferon InterferonLymphoblastoid GlaxoSmithKline IFN-αn1 plc, Uxbridge, UK OmniferonInterferon natural IFN-α Viragen Inc., Plantation, FL Pegasys InterferonPEGylated IFN- F. Hoffmann-La α2a Roche LTD, Basel, Switzerland Pegasysand Interferon PEGylated IFN- Maxim Ceplene α2a/immune Pharmaceuticalsmodulator Inc., San Diego, CA Pegasys and Interferon PEGylated IFN- F.Hoffmann-La Ribavirin α2a/ribavirin Roche LTD, Basel, SwitzerlandPEG-Intron Interferon PEGylated IFN- Schering-Plough α2b Corporation,Kenilworth, NJ PEG-Intron/ Interferon PEGylated IFN- Schering-PloughRibavirin α2b/ribavirin Corporation, Kenilworth, NJ IP-501 LiverAntifibrotic Indevus protection Pharmaceuticals Inc., Lexington, MAIDN-6556 Liver Caspase Idun protection inhibitor Pharmaceuticals Inc.,San Diego, CA ITMN-191 Antiviral Serine protease InterMune (R-7227)inhibitor Pharmaceuticals Inc., Brisbane, CA GL-59728 Antiviral NS5Breplicase Genelabs inhibitor ANA-971 Antiviral TLR-7 agonist AnadysBoceprevir Antiviral Serine protease Schering Plough inhibitor TMS-435Antiviral Serine protease Tibotec BVBA, inhibitor Mechelen, BelgiumBI-201335 Antiviral Serine protease Boehringer inhibitor IngelheimPharma KG, Ingelheim, Germany MK-7009 Antiviral Serine protease Merckinhibitor PF-00868554 Antiviral Replicase Pfizer inhibitor ANA598Antiviral Non-Nucleoside Anadys NS5B Pharmaceuticals, polymerase Inc.,San Diego, CA, inhibitor USA IDX375 Antiviral Non-Nucleoside Idenixreplicase Pharmaceuticals, inhibitor Cambridge, MA, USA BILB 1941Antiviral NS5B Boehringer polymerase Ingelheim Canada inhibitor Ltd R&D,Laval, QC, Canada PSI-7851 Antiviral Nucleoside Pharmasset, polymerasePrinceton, NJ, USA inhibitor VCH-759 Antiviral NS5B ViroChem Pharmapolymerase inhibitor VCH-916 Antiviral NS5B ViroChem Pharma polymeraseinhibitor GS-9190 Antiviral NS5B Gilead polymerase inhibitorPeg-interferon Antiviral Interferon ZymoGenetics/ lamda Bristol-MyersSquibb

The compounds of the present disclosure may also be used as laboratoryreagents. Compounds may be instrumental in providing research tools fordesigning of viral replication assays, validation of animal assaysystems and structural biology studies to further enhance knowledge ofthe HCV disease mechanisms. Further, the compounds of the presentdisclosure are useful in establishing or determining the binding site ofother antiviral compounds, for example, by competitive inhibition.

The compounds of this disclosure may also be used to treat or preventviral contamination of materials and therefore reduce the risk of viralinfection of laboratory or medical personnel or patients who come incontact with such materials, e.g., blood, tissue, surgical instrumentsand garments, laboratory instruments and garments, and blood collectionor transfusion apparatuses and materials.

This disclosure is intended to encompass compounds having Formula (I)when prepared by synthetic processes or by metabolic processes includingthose occurring in the human or animal body (in vivo) or processesoccurring in vitro.

The abbreviations used in the present application, includingparticularly in the illustrative examples which follow, are well-knownto those skilled in the art. Some of the abbreviations used are asfollows:

-   Me methyl-   Et ethyl;-   t-Bu tert-butyl;-   iPr isopropyl;-   min minutes;-   rt or RT room temperature or retention time (context will dictate);-   TFA trifluoroacetic acid;-   h or hr hours;-   DMSO dimethylsulfoxide;-   DME dimethyl ether;-   LDA Lithium diisopropylamide;-   NBS N-Bromosuccinimide;-   SEM-Cl 2-(Trimethylsilyl)ethoxymethyl chloride;-   TBAF tetrabutylammonium fluoride;-   HATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium    hexafluorophosphate;-   iPr₂EtN diisopropylethylamine;-   DIEA diisopropylethylamine;-   DIPEA diisopropylethylamine;-   Hunig's diisopropylethylamine;-   Boc or BOC tert-butoxycarbonyl;-   DMAP 4-dimethylaminopyridine;-   HCl hydrochloric acid;-   Na₂SO₄ sodium sulfate;-   MgSO₄ magnesium sulfate;-   PdCl₂(PPh₃)₂ bis(triphenylphosphine)palladium(II)dichloride; MCX-   cartridge Waters Oasis® MCX LP extraction cartridge.

The present disclosure will now be described in connection with certainembodiments which are not intended to limit its scope. On the contrary,the present disclosure covers all alternatives, modifications, andequivalents as can be included within the scope of the claims. Thus, thefollowing examples, which include specific embodiments, will illustrateone practice of the present disclosure, it being understood that theexamples are for the purposes of illustration of certain embodiments andare presented to provide what is believed to be the most useful andreadily understood description of its procedures and conceptual aspects.

Starting materials can be obtained from commercial sources or preparedby well-established literature methods known to those of ordinary skillin the art.

SYNTHETIC METHODS Scheme 1: Substituted Phenylglycine Derivatives

Substituted phenylglycine derivatives can be prepared by a number ofmethods shown below. Phenylglycine t-butyl ester can be reductivelyalkylated (pathway A) with an appropriate aldehyde and a reductant suchas sodium cyanoborohydride in acidic medium. Hydrolysis of the t-butylester can be accomplished with strong acid such as HCl ortrifluoroacetic acid. Alternatively, phenylglycine can be alkylated withan alkyl halide such as ethyl iodide and a base such as sodiumbicarbonate or potassium carbonate (pathway B). Pathway C illustratesreductive alkylation of phenylglycine as in pathway A followed by asecond reductive alkylation with an alternate aldehyde such asformaldehyde in the presence of a reducing agent and acid. Pathway Dillustrates the synthesis of substituted phenylglycines via thecorresponding mandelic acid analogs. Conversion of the secondary alcoholto a competent leaving group can be accomplished with p-toluensulfonylchloride. Displacement of the tosylate group with an appropriate aminefollowed by reductive removal of the benzyl ester can providesubstituted phenylglycine derivatives. In pathway E a racemicsubstituted phenylglycine derivative is resolved by esterification withan enantiomerically pure chiral auxiliary such as but not limited to(+)-1-phenylethanol, (−)-1-phenylethanol, an Evan's oxazolidinone, orenantiomerically pure pantolactone. Separation of the diastereomers isaccomplished via chromatography (silica gel, HPLC, crystallization, etc)followed by removal of the chiral auxiliary providing enantiomericallypure phenylglycine derivatives. Pathway H illustrates a syntheticsequence which intersects with pathway E wherein the aforementionedchiral auxiliary is installed prior to amine addition. Alternatively, anester of an arylacetic acid can be brominated with a source of bromoniumion such as bromine, N-bromosuccinimide, or CBr₄. The resultant benzylicbromide can be displaced with a variety of mono- or disubstituted aminesin the presence of a tertiary amine base such as triethylamine orHunig's base. Hydrolysis of the methyl ester via treatment with lithiumhydroxide at low temperature or 6N HCl at elevated temperature providesthe substituted phenylglycine derivatives. Another method is shown inpathway G. Glycine analogs can be derivatized with a variety of arylhalides in the presence of a source of palladium (0) such as palladiumbis(tributylphosphine) and base such as potassium phosphate. Theresultant ester can then be hydrolyzed by treatment with base or acid.It should be understood that other well known methods to preparephenylglycine derivatives exist in the art and can be amended to providethe desired compounds in this description. It should also be understoodthat the final phenylglycine derivatives can be purified to enantiomericpurity greater than 98% ee via preparative HPLC.

In another embodiment of the present disclosure, acylated phenylglycinederivatives may be prepared as illustrated below. Phenylglycinederivatives wherein the carboxylic acid is protected as an easilyremoved ester, may be acylated with an acid chloride in the presence ofa base such as triethylamine to provide the corresponding amides(pathway A). Pathway B illustrates the acylation of the startingphenylglycine derivative with an appropriate chloroformate while pathwayC shows reaction with an appropriate isocyanate or carbamoyl chloride.Each of the three intermediates shown in pathways A-C may be deprotectedby methods known by those skilled in the art (ie; treatment of thet-butyl ester with strong base such as HCl or trifluoroacetic acid).

Amino-substituted phenylacetic acids may be prepared by treatment of achloromethylphenylacetic acid with an excess of an amine

SYNTHESIS OF COMMON CAPS Compound Analysis Conditions

Purity assessment and low resolution mass analysis were conducted on aShimadzu LC system coupled with Waters MICROMASS® ZQ MS system. Itshould be noted that retention times may vary slightly between machines.Additional LC conditions applicable to the current section, unless notedotherwise.

Cond.-MS-W1

-   Column=XTERRA® 3.0×50 mm S7-   Start % B=0-   Final % B=100-   Gradient time=2 min-   Stop time=3 min-   Flow Rate=5 mL/min-   Wavelength=220 nm-   Solvent A=0.1% TFA in 10% methanol/90% H₂O-   Solvent B=0.1% TFA in 90% methanol/10% H₂O    Cond.-MS-W2-   Column=XTERRA® 3.0×50 mm S7-   Start % B=0-   Final % B=100-   Gradient time=3 min-   Stop time=4 min-   Flow Rate=4 mL/min-   Wavelength=220 nm-   Solvent A=0.1% TFA in 10% methanol/90% H₂O-   Solvent B=0.1% TFA in 90% methanol/10% H₂O    Cond.-MS-W5-   Column=XTERRA® 3.0×50 mm S7-   Start % B=0-   Final % B=30-   Gradient time=2 min-   Stop time=3 min-   Flow Rate=5 mL/min-   Wavelength=220 nm-   Solvent A=0.1% TFA in 10% methanol/90% H₂O-   Solvent B=0.1% TFA in 90% methanol/10% H₂O    Cond.-D1-   Column=XTERRA® C18 3.0×50 mm S7-   Start % B=0-   Final % B=100-   Gradient time=3 min-   Stop time=4 min-   Flow Rate=4 mL/min-   Wavelength=220 nm-   Solvent A=0.1% TFA in 10% methanol/90% H₂O-   Solvent B=0.1% TFA in 90% methanol/10% H₂O    Cond.-D2-   Column=PHENOMENEX® Luna 4.6×50 mm S10-   Start % B=0-   Final % B=100-   Gradient time=3 min-   Stop time=4 min-   Flow Rate=4 mL/min-   Wavelength=220 nm-   Solvent A=0.1% TFA in 10% methanol/90% H₂O-   Solvent B=0.1% TFA in 90% methanol/10% H₂O    Cond.-M3-   Column=XTERRA® C18 3.0×50 mm S7-   Start % B=0-   Final % B=40-   Gradient time=2 min-   Stop time=3 min-   Flow Rate=5 mL/min-   Wavelength=220 nm-   Solvent A=0.1% TFA in 10% methanol/90% H₂O-   Solvent B=0.1% TFA in 90% methanol/10% H₂O    Condition I-   Column=PHENOMENEX® Luna 3.0×50 mm S10-   Start % B=0

Final % B=100

-   Gradient time=2 min-   Stop time=3 min-   Flow Rate=4 mL/min-   Wavelength=220 nm-   Solvent A=0.1% TFA in 10% methanol/90% H₂O-   Solvent B=0.1% TFA in 90% methanol/10% H₂O    Condition II-   Column=PHENOMENEX® Luna 4.6×50 mm S10-   Start % B=0-   Final % B=100-   Gradient time=2 min-   Stop time=3 min-   Flow Rate=5 mL/min-   Wavelength=220 nm-   Solvent A=0.1% TFA in 10% methanol/90% H₂O-   Solvent B=0.1% TFA in 90% methanol/10% H₂O    Condition III-   Column=XTERRA® C18 3.0×50 mm S7-   Start % B=0-   Final % B=100-   Gradient time=3 min-   Stop time=4 min-   Flow Rate=4 mL/min-   Wavelength=220 nm-   Solvent A=0.1% TFA in 10% methanol/90% H₂O-   Solvent B=0.1% TFA in 90% methanol/10% H₂O

Cap-1

(R)-2-(Dimethylamino)-2-phenylacetic acid

A suspension of 10% Pd/C (2.0 g) in methanol (10 mL) was added to amixture of (R)-2-phenylglycine (10 g, 66.2 mmol), formaldehyde (33 mL of37% wt. in water), 1N HCl (30 mL) and methanol (30 mL), and exposed toH₂ (60 psi) for 3 hours. The reaction mixture was filtered throughdiatomaceous earth (CELITE®), and the filtrate was concentrated invacuo. The resulting crude material was recrystallized from isopropanolto provide the HCl salt of Cap-1 as a white needle (4.0 g). Opticalrotation: −117.1° [c=9.95 mg/mL in H₂O; λ=589 nm]. ¹H NMR (DMSO-d₆,δ=2.5 ppm, 500 MHz): δ 7.43-7.34 (m, 5H), 4.14 (s, 1H), 2.43 (s, 6H); LC(Condition I): RT=0.25; LC-MS: Anal. Calcd. for [M+H]⁺ C₁₀H₁₄NO₂ 180.10.found 180.17. HRMS: Anal. Calcd. for [M+H]⁺ C₁₀H₁₄NO₂ 180.1025; found180.1017.

Cap-2

(R)-2-(Diethylamino)-2-phenylacetic acid

NaBH₃CN (6.22 g, 94 mmol) was added in portions over a few minutes to acooled (ice/water) mixture of (R)-2-Phenylglycine (6.02 g, 39.8 mmol)and methanol (100 mL), and stirred for 5 minutes. Acetaldehyde (10 mL)was added dropwise over 10 minutes and stirring was continued at thesame cooled temperature for 45 minutes and at ambient temperature for˜6.5 hours. The reaction mixture was cooled back with ice-water bath,treated with water (3 mL) and then quenched with a dropwise addition ofconcentrated HCl over ˜45 minutes until the pH of the mixture was˜1.5-2.0. The cooling bath was removed and the stirring was continuedwhile adding concentrated HCl in order to maintain the pH of the mixturearound 1.5-2.0. The reaction mixture was stirred overnight, filtered toremove the white suspension, and the filtrate was concentrated in vacuo.The crude material was recrystallized from ethanol to afford the HClsalt of Cap-2 as a shining white solid in two crops (crop-1: 4.16 g;crop-2: 2.19 g). ¹H NMR (DMSO-d₆, δ=2.5 ppm, 400 MHz): 10.44 (1.00, brs, 1H), 7.66 (m, 2H), 7.51 (m, 3H), 5.30 (s, 1H), 3.15 (br m, 2H), 2.98(br m, 2H), 1.20 (app br s, 6H). Crop-1: [α]²⁵ −102.21° (c=0.357, H₂O);crop-2: [α]²⁵ −99.7° (c=0.357, H₂O). LC (Condition I): RT=0.43 min;LC-MS: Anal. Calcd. for [M+H]⁺ C₁₂H₁₈NO₂: 208.13; found 208.26.

Cap-3

Acetaldehyde (5.0 mL, 89.1 mmol) and a suspension of 10% Pd/C (720 mg)in methanol/H₂O (4 mL/1 mL) was sequentially added to a cooled (˜15° C.)mixture of (R)-2-phenylglycine (3.096 g, 20.48 mmol), 1N HCl (30 mL) andmethanol (40 mL). The cooling bath was removed and the reaction mixturewas stirred under a balloon of H₂ for 17 hours. An additionalacetaldehyde (10 mL, 178.2 mmol) was added and stirring continued underH₂ atmosphere for 24 hours [Note: the supply of H₂ was replenished asneeded throughout the reaction]. The reaction mixture was filteredthrough diatomaceous earth (CELITE®), and the filtrate was concentratedin vacuo. The resulting crude material was recrystallized fromisopropanol to provide the HCl salt of (R)-2-(ethylamino)-2-phenylaceticacid as a shining white solid (2.846 g). ¹H NMR (DMSO-d₆, δ=2.5 ppm, 400MHz): δ 14.15 (br s, 1H), 9.55 (br s, 2H), 7.55-7.48 (m, 5H), 2.88 (brm, 1H), 2.73 (br m, 1H), 1.20 (app t, J=7.2, 3H). LC (Condition I):RT=0.39 min; >95% homogeneity index; LC-MS: Anal. Calcd. for [M+H]⁺C₁₀H₁₄NO₂: 180.10; found 180.18.

A suspension of 10% Pd/C (536 mg) in methanol/H₂O (3 mL/1 mL) was addedto a mixture of (R)-2-(ethylamino)-2-phenylacetic acid/HCl (1.492 g,6.918 mmol), formaldehyde (20 mL of 37% wt. in water), 1N HCl (20 mL)and methanol (23 mL). The reaction mixture was stirred under a balloonof H₂ for ˜72 hours, where the H₂ supply was replenished as needed. Thereaction mixture was filtered through diatomaceous earth (CELITE®) andthe filtrate was concentrated in vacuo. The resulting crude material wasrecrystallized from isopropanol (50 mL) to provide the HCl salt of Cap-3as a white solid (985 mg). ¹H NMR (DMSO-d₆, δ=2.5 ppm, 400 MHz): δ 10.48(br s, 1H), 7.59-7.51 (m, 5H), 5.26 (s, 1H), 3.08 (app br s, 2H), 2.65(br s, 3H), 1.24 (br m, 3H). LC (Condition I): RT=0.39 min; >95%homogeneity index; LC-MS: Anal. Calcd. for [M+H]⁺ C₁₁H₁₆NO₂: 194.12;found 194.18; HRMS: Anal. Calcd. for [M+H]⁺ C₁₁H₁₆NO₂: 194.1180; found194.1181.

Cap-4

(R)-2-(Methoxycarbonylamino)-2-phenylacetic acid

ClCO₂Me (3.2 mL, 41.4 mmol) was added dropwise to a cooled (ice/water)THF (410 mL) semi-solution of (R)-tert-butyl 2-amino-2-phenylacetate/HCl(9.877 g, 40.52 mmol) and diisopropylethylamine (14.2 mL, 81.52 mmol)over 6 min, and stirred at similar temperature for 5.5 hours. Thevolatile component was removed in vacuo, and the residue was partitionedbetween water (100 mL) and ethyl acetate (200 mL). The organic layer waswashed with 1N HCl (25 mL) and saturated NaHCO₃ solution (30 mL), dried(MgSO₄), filtered, and concentrated in vacuo. The resultant colorlessoil was triturated from hexanes, filtered and washed with hexanes (100mL) to provide (R)-tert-butyl 2-(methoxycarbonylamino)-2-phenylacetateas a white solid (7.7 g). ¹H NMR (DMSO-d₆, δ=2.5 ppm, 400 MHz): 7.98 (d,J=8.0, 1H), 7.37-7.29 (m, 5H), 5.09 (d, J=8, 1H), 3.56 (s, 3H), 1.33 (s,9H). LC (Condition I): RT=1.53 min; ˜90% homogeneity index; LC-MS: Anal.Calcd. for [M+Na]⁺ C₁₄H₁₉NNaO₄: 288.12; found 288.15.

TFA (16 mL) was added dropwise to a cooled (ice/water) CH₂Cl₂ (160 mL)solution of the above product over 7 minutes, and the cooling bath wasremoved and the reaction mixture was stirred for 20 hours. Since thedeprotection was still not complete, an additional TFA (1.0 mL) wasadded and stirring continued for an additional 2 hours. The volatilecomponent was removed in vacuo, and the resulting oil residue wastreated with diethyl ether (15 mL) and hexanes (12 mL) to provide aprecipitate. The precipitate was filtered and washed with diethylether/hexanes (˜1:3 ratio; 30 mL) and dried in vacuo to provide Cap-4 asa fluffy white solid (5.57 g). Optical rotation: −176.9° [c=3.7 mg/mL inH₂O; λ==589 nm]. ¹H NMR (DMSO-d₆, δ=2.5 ppm, 400 MHz): δ 12.84 (br s,1H), 7.96 (d, J=8.3, 1H), 7.41-7.29 (m, 5H), 5.14 (d, J=8.3, 1H), 3.55(s, 3H). LC (Condition I): RT=1.01 min; >95% homogeneity index; LC-MS:Anal. Calcd. for [M+H]⁺ C₁₀H₁₂NO₄ 210.08; found 210.17; HRMS: Anal.Calcd. for [M+H]⁺ C₁₀H₁₂NO₄ 210.0766; found 210.0756.

Cap-5

A mixture of (R)-2-phenylglycine (1.0 g, 6.62 mmol), 1,4-dibromobutane(1.57 g, 7.27 mmol) and Na₂CO₃ (2.10 g, 19.8 mmol) in ethanol (40 mL)was heated at 100° C. for 21 hours. The reaction mixture was cooled toambient temperature and filtered, and the filtrate was concentrated invacuo. The residue was dissolved in ethanol and acidified with 1N HCl topH 3-4, and the volatile component was removed in vacuo. The resultingcrude material was purified by a reverse phase HPLC (water/methanol/TFA)to provide the TFA salt of Cap-5 as a semi-viscous white foam (1.0 g).¹H NMR (DMSO-d₆, δ=2.5, 500 MHz) δ 10.68 (br s, 1H), 7.51 (m, 5H), 5.23(s, 1H), 3.34 (app br s, 2H), 3.05 (app br s, 2H), 1.95 (app br s, 4H);RT=0.30 minutes (Condition I); >98% homogeneity index; LC-MS: Anal.Calcd. for [M+H]⁺ C₁₂H₁₆NO₂: 206.12; found 206.25.

Cap-6

The TFA salt of Cap-6 was synthesized from (R)-2-phenylglycine and1-bromo-2-(2-bromoethoxy)ethane by using the method of preparation ofCap-5. ¹H NMR (DMSO-d₆, δ=2.5, 500 MHz) δ 12.20 (br s, 1H), 7.50 (m,5H), 4.92 (s, 1H), 3.78 (app br s, 4H), 3.08 (app br s, 2H), 2.81 (appbr s, 2H); RT=0.32 minutes (Condition I); >98%; LC-MS: Anal. Calcd. for[M+H]⁺ C₁₂H₁₆NO₃: 222.11; found 222.20; HRMS: Anal. Calcd. for [M+H]⁺C₁₂H₁₆NO₃: 222.1130; found 222.1121.

Cap-7

A CH₂Cl₂ (200 mL) solution of p-toluenesulfonyl chloride (8.65 g, 45.4mmol) was added dropwise to a cooled (−5° C.) CH₂Cl₂ (200 mL) solutionof (S)-benzyl 2-hydroxy-2-phenylacetate (10.0 g, 41.3 mmol),triethylamine (5.75 mL, 41.3 mmol) and 4-dimethylaminopyridine (0.504 g,4.13 mmol), while maintaining the temperature between −5° C. and 0° C.The reaction was stirred at 0° C. for 9 hours, and then stored in afreezer (−25° C.) for 14 hours. It was allowed to thaw to ambienttemperature and washed with water (200 mL), 1N HCl (100 mL) and brine(100 mL), dried (MgSO₄), filtered, and concentrated in vacuo to providebenzyl 2-phenyl-2-(tosyloxy)acetate as a viscous oil which solidifiedupon standing (16.5 g). The chiral integrity of the product was notchecked and that product was used for the next step without furtherpurification. ¹H NMR (DMSO-d₆, δ=2.5, 500 MHz) δ 7.78 (d, J=8.6, 2H),7.43-7.29 (m, 10H), 7.20 (m, 2H), 6.12 (s, 1H), 5.16 (d, J=12.5, 1H),5.10 (d, J=12.5, 1H), 2.39 (s, 3H). RT=3.00 (Condition III); >90%homogeneity index; LC-MS: Anal. Calcd. for [M+H]⁺ C₂₂H₂₀NaO₅S: 419.09;found 419.04.

A THF (75 mL) solution of benzyl 2-phenyl-2-(tosyloxy)acetate (6.0 g,15.1 mmol), 1-methylpiperazine (3.36 mL, 30.3 mmol) andN,N-diisopropylethylamine (13.2 mL, 75.8 mmol) was heated at 65° C. for7 hours. The reaction was allowed to cool to ambient temperature and thevolatile component was removed in vacuo. The residue was partitionedbetween ethylacetate and water, and the organic layer was washed withwater and brine, dried (MgSO₄), filtered, and concentrated in vacuo. Theresulting crude material was purified by flash chromatography (silicagel, ethyl acetate) to provide benzyl2-(4-methylpiperazin-1-yl)-2-phenylacetate as an orangish-brown viscousoil (4.56 g). Chiral HPLC analysis (CHIRALCEL® OD-H) indicated that thesample is a mixture of stereoisomers in a 38.2 to 58.7 ratio. Theseparation of the stereoisomers were effected as follow: the product wasdissolved in 120 mL of ethanol/heptane (1:1) and injected (5mL/injection) on chiral HPLC column (Chiracel OJ, 5 cm ID×50 cm L, 20μm) eluting with 85:15 Heptane/ethanol at 75 mL/min, and monitored at220 nm. Stereoisomer-1 (1.474 g) and stereoisomer-2 (2.2149 g) wereretrieved as viscous oil. ¹H NMR (CDCl₃, δ=7.26, 500 MHz) 7.44-7.40 (m,2H), 7.33-7.24 (m, 6H), 7.21-7.16 (m, 2H), 5.13 (d, J=12.5, 1H), 5.08(d, J=12.5, 1H), 4.02 (s, 1H), 2.65-2.38 (app br s, 8H), 2.25 (s, 3H).RT=2.10 (Condition III); >98% homogeneity index; LC-MS: Anal. Calcd. for[M+H]⁺ C₂₀H₂₅N₂O₂: 325.19; found 325.20.

A methanol (10 mL) solution of either stereoisomer of benzyl2-(4-methylpiperazin-1-yl)-2-phenylacetate (1.0 g, 3.1 mmol) was addedto a suspension of 10% Pd/C (120 mg) in methanol (5.0 mL). The reactionmixture was exposed to a balloon of hydrogen, under a carefulmonitoring, for <50 minutes. Immediately after the completion of thereaction, the catalyst was filtered through diatomaceous earth (CELITE®)and the filtrate was concentrated in vacuo to provide Cap-7,contaminated with phenylacetic acid as a tan foam (867.6 mg; mass isabove the theoretical yield). The product was used for the next stepwithout further purification. ¹H NMR (DMSO-d₆, δ=2.5, 500 MHz) δ7.44-7.37 (m, 2H), 7.37-7.24 (m, 3H), 3.92 (s, 1H), 2.63-2.48 (app. brs, 2H), 2.48-2.32 (m, 6H), 2.19 (s, 3H); RT=0.31 (Condition II); >90%homogeneity index; LC-MS: Anal. Calcd. for [M+H]⁺ C₁₃H₁₉N₂O₂: 235.14;found 235.15; HRMS: Anal. Calcd. for [M+H]⁺ C₁₃H₁₉N₂O₂: 235.1447; found235.1440.

The synthesis of Cap-8 and Cap-9 was conducted according to thesynthesis of Cap-7 by using appropriate amines for the SN₂ displacementstep (i.e., 4-hydroxypiperidine for Cap-8 and (S)-3-fluoropyrrolidinefor Cap-9) and modified conditions for the separation of the respectivestereoisomeric intermediates, as described below.

Cap-8

The stereoisomeric separation of the intermediate benzyl2-(4-hydroxypiperidin-1-yl)-2-phenyl acetate was effected by employingthe following conditions: the compound (500 mg) was dissolved inethanol/heptane (5 mL/45 mL). The resulting solution was injected (5mL/injection) on a chiral HPLC column (Chiracel OJ, 2 cm ID×25 cm L, 10μm) eluting with 80:20 heptane/ethanol at 10 mL/min, monitored at 220nm, to provide 186.3 mg of stereoisomer-1 and 209.1 mg of stereoisomer-2as light-yellow viscous oils. These benzyl ester was hydrogenolysedaccording to the preparation of Cap-7 to provide Cap-8: ¹H NMR (DMSO-d₆,δ=2.5, 500 MHz) 7.40 (d, J=7, 2H), 7.28-7.20 (m, 3H), 3.78 (s 1H), 3.46(m, 1H), 2.93 (m, 1H), 2.62 (m, 1H), 2.20 (m, 2H), 1.70 (m, 2H), 1.42(m, 2H). RT=0.28 (Condition II); >98% homogeneity index; LC-MS: Anal.Calcd. for [M+H]⁺ C₁₃H₁₈NO₃: 236.13; found 236.07; HRMS: Calcd. for[M+H]⁺ C₁₃H₁₈NO₃: 236.1287. found 236.1283.

Cap-9

The diastereomeric separation of the intermediate benzyl2-((S)-3-fluoropyrrolidin-1-yl)-2-phenylacetate was effected byemploying the following conditions: the ester (220 mg) was separated ona chiral HPLC column (Chiracel OJ-H, 0.46 cm ID×25 cm L, 5 μm) elutingwith 95% CO₂/5% methanol with 0.1% TFA, at 10 bar pressure, 70 mL/minflow rate, and a temperature of 35° C. The HPLC elute for the respectivestereoisomers was concentrated, and the residue was dissolved in CH₂Cl₂(20 mL) and washed with an aqueous medium (10 mL water+1 mL saturatedNaHCO₃ solution). The organic phase was dried (MgSO₄), filtered, andconcentrated in vacuo to provide 92.5 mg of fraction-1 and 59.6 mg offraction-2. These benzyl esters were hydrogenolysed according to thepreparation of Cap-7 to prepare Cap-9a and Cap-9b. Cap-9a(diastereomer-1; the sample is a TFA salt as a result of purification ona reverse phase HPLC using H₂O/methanol/TFA solvent): ¹H NMR (DMSO-d₆,δ=2.5, 400 MHz) 7.55-7.48 (m, 5H), 5.38 (d of m, J=53.7, 1H), 5.09 (brs, 1H), 3.84-2.82 (br m, 4H), 2.31-2.09 (m, 2H). RT=0.42 (ConditionI); >95% homogeneity index; LC-MS: Anal. Calcd. for [M+H]⁺ C₁₂H₁₅FNO₂:224.11; found 224.14; Cap-9b (diastereomer-2): ¹H NMR (DMSO-d₆, δ=2.5,400 MHz) 7.43-7.21 (m, 5H), 5.19 (d of m, J=55.9, 1H), 3.97 (s, 1H),2.95-2.43 (m, 4H), 2.19-1.78 (m, 2H). RT=0.44 (Condition I); LC-MS:Anal. Calcd. for [M+H]⁺ C₁₂H₁₅FNO₂: 224.11; found 224.14.

Cap-10

To a solution of D-proline (2.0 g, 17 mmol) and formaldehyde (2.0 mL of37% wt. in H₂O) in methanol (15 mL) was added a suspension of 10% Pd/C(500 mg) in methanol (5 mL). The mixture was stirred under a balloon ofhydrogen for 23 hours. The reaction mixture was filtered throughdiatomaceous earth (CELITE®) and concentrated in vacuo to provide Cap-10as an off-white solid (2.15 g). ¹H NMR (DMSO-d₆, δ=2.5, 500 MHz) 3.42(m, 1H), 3.37 (dd, J=9.4, 6.1, 1H), 2.85-2.78 (m, 1H), 2.66 (s, 3H),2.21-2.13 (m, 1H), 1.93-1.84 (m, 2H), 1.75-1.66 (m, 1H). RT=0.28(Condition II); >98% homogeneity index; LC-MS: Anal. Calcd. for [M+H]⁺C₆H₁₂NO₂: 130.09; found 129.96.

Cap-11

A mixture of (2S,4R)-4-fluoropyrrolidine-2-carboxylic acid (0.50 g, 3.8mmol), formaldehyde (0.5 mL of 37% wt. in H₂O), 12 N HCl (0.25 mL) and10% Pd/C (50 mg) in methanol (20 mL) was stirred under a balloon ofhydrogen for 19 hours. The reaction mixture was filtered throughdiatomaceous earth (CELITE®) and the filtrate was concentrated in vacuo.The residue was recrystallized from isopropanol to provide the HCl saltof Cap-11 as a white solid (337.7 mg). ¹H NMR (DMSO-d₆, δ=2.5, 500 MHz)5.39 (d m, J=53.7, 1H), 4.30 (m, 1H), 3.90 (ddd, J=31.5, 13.5, 4.5, 1H),3.33 (dd, J=25.6, 13.4, 1H), 2.85 (s, 3H), 2.60-2.51 (m, 1H), 2.39-2.26(m, 1H). RT=0.28 (Condition II); >98% homogeneity index; LC-MS: Anal.Calcd. for [M+H]⁺ C₆H₁₁FNO₂: 148.08; found 148.06.

Cap-12 Same as Cap-52

(S)-2-(Methoxycarbonylamino)propanoic acid

L-Alanine (2.0 g, 22.5 mmol) was dissolved in 10% aqueous sodiumcarbonate solution (50 mL), and a THF (50 mL) solution of methylchloroformate (4.0 mL) was added to it. The reaction mixture was stirredunder ambient conditions for 4.5 hours and concentrated in vacuo. Theresulting white solid was dissolved in water and acidified with 1N HClto a pH ˜2-3. The resulting solutions was extracted with ethyl acetate(3×100 mL), and the combined organic phase was dried (Na₂SO₄), filtered,and concentrated in vacuo to provide a colorless oil (2.58 g). 500 mg ofthis material was purified by a reverse phase HPLC (H₂O/methanol/TFA) toprovide 150 mg of Cap-12 as a colorless oil. ¹H NMR (DMSO-d₆, δ=2.5, 500MHz) 7.44 (d, J=7.3, 0.8H), 7.10 (br s, 0.2H), 3.97 (m, 1H), 3.53 (s,3H), 1.25 (d, J=7.3, 3H).

Cap-13

A mixture of L-alanine (2.5 g, 28 mmol), formaldehyde (8.4 g, 37 wt. %),1N HCl (30 mL) and 10% Pd/C (500 mg) in methanol (30 mL) was stirredunder a hydrogen atmosphere (50 psi) for 5 hours. The reaction mixturewas filtered through diatomaceous earth (CELITE®) and the filtrate wasconcentrated in vacuo to provide the HCl salt of Cap-13 as an oil whichsolidified upon standing under vacuum (4.4 g; the mass is abovetheoretical yield). The product was used without further purification.¹H NMR (DMSO-d₆, δ=2.5, 500 MHz) δ 12.1 (br s, 1H), 4.06 (q, J=7.4, 1H),2.76 (s, 6H), 1.46 (d, J=7.3, 3H).

Cap-14

(R)-2-Phenyl-2-(piperidin-1-yl)acetic acid

Step 1: A mixture of (R)-(−)-D-phenylglycine tert-butyl ester (3.00 g,12.3 mmol), NaBH₃CN (0.773 g, 12.3 mmol), KOH (0.690 g, 12.3 mmol) andacetic acid (0.352 mL, 6.15 mmol) were stirred in methanol at 0° C. Tothis mixture was added glutaric dialdehyde (2.23 mL, 12.3 mmol) dropwiseover 5 minutes. The reaction mixture was stirred as it was allowed towarm to ambient temperature and stirring was continued at the sametemperature for 16 hours. The solvent was subsequently removed and theresidue was partitioned with 10% aqueous NaOH and ethyl acetate. Theorganic phase was separated, dried (MgSO₄), filtered and concentrated todryness to provide a clear oil. This material was purified byreverse-phase preparative HPLC (Primesphere C-18, 30×100 mm;CH₃CN—H₂O-0.1% TFA) to give the intermediate ester (2.70 g, 56%) as aclear oil. ¹H NMR (400 MHz, CDCl₃) δ 7.53-7.44 (m, 3H), 7.40-7.37 (m,2H), 3.87 (d, J=10.9 Hz, 1H), 3.59 (d, J=10.9 Hz, 1H), 2.99 (t, J=11.2Hz, 1H), 2.59 (t, J=11.4 Hz, 1H), 2.07-2.02 (m, 2H), 1.82 (d, J=1.82 Hz,3H), 1.40 (s, 9H). LC-MS: Anal. Calcd. for C₁₇H₂₅NO₂: 275; found: 276(M+H)⁺.

Step 2: To a stirred solution of the intermediate ester (1.12 g, 2.88mmol) in dichloromethane (10 mL) was added TFA (3 mL). The reactionmixture was stirred at ambient temperature for 4 hours and then it wasconcentrated to dryness to give a light yellow oil. The oil was purifiedusing reverse-phase preparative HPLC (Primesphere C-18, 30×100 mm;CH₃CN—H₂O-0.1% TFA). The appropriate fractions were combined andconcentrated to dryness in vacuo. The residue was then dissolved in aminimum amount of methanol and applied to applied to MCX LP extractioncartridges (2×6 g). The cartridges were rinsed with methanol (40 mL) andthen the desired compound was eluted using 2M ammonia in methanol (50mL). Product-containing fractions were combined and concentrated and theresidue was taken up in water. Lyophilization of this solution providedthe title compound (0.492 g, 78%) as a light yellow solid. ¹H NMR(DMSO-d₆) δ 7.50 (s, 5H), 5.13 (s, 1H), 3.09 (br s, 2H), 2.92-2.89 (m,2H), 1.74 (m, 4H), 1.48 (br s, 2H). LC-MS: Anal. Calcd. for C₁₃H₁₇NO₂:219; found: 220 (M+H)⁺.

Cap-15

Step 1: (S)-1-Phenylethyl 2-bromo-2-phenylacetate. To a mixture ofα-bromophenylacetic acid (10.75 g, 0.050 mol), (S)-(−)-1-phenylethanol(7.94 g, 0.065 mol) and DMAP (0.61 g, 5.0 mmol) in dry dichloromethane(100 mL) was added solid EDCI (12.46 g, 0.065 mol) all at once. Theresulting solution was stirred at room temperature under Ar for 18 hoursand then it was diluted with ethyl acetate, washed (H₂O×2, brine), dried(Na₂SO₄), filtered, and concentrated to give a pale yellow oil. Flashchromatography (SiO₂/hexane-ethyl acetate, 4:1) of this oil provided thetitle compound (11.64 g, 73%) as a white solid. ¹H NMR (400 MHz, CDCl₃)δ 7.53-7.17 (m, 10H), 5.95 (q, J=6.6 Hz, 0.5H), 5.94 (q, J=6.6 Hz,0.5H), 5.41 (s, 0.5H), 5.39 (s, 0.5H), 1.58 (d, J=6.6 Hz, 1.5H), 1.51(d, J=6.6 Hz, 1.5H).

Step 2:(S)-1-Phenylethyl(R)-2-(4-hydroxy-4-methylpiperidin-1-yl)-2-phenylacetate.To a solution of (S)-1-phenylethyl 2-bromo-2-phenylacetate (0.464 g,1.45 mmol) in THF (8 mL) was added triethylamine (0.61 mL, 4.35 mmol),followed by tetrabutylammonium iodide (0.215 g, 0.58 mmol). The reactionmixture was stirred at room temperature for 5 minutes and then asolution of 4-methyl-4-hydroxypiperidine (0.251 g, 2.18 mmol) in THF (2mL) was added. The mixture was stirred for 1 hour at room temperatureand then it was heated at 55-60° C. (oil bath temperature) for 4 hours.The cooled reaction mixture was then diluted with ethyl acetate (30 mL),washed (H₂O×2, brine), dried (MgSO₄), filtered and concentrated. Theresidue was purified by silica gel chromatography (0-60% ethylacetate-hexane) to provide first the (S,R)-isomer of the title compound(0.306 g, 60%) as a white solid and then the corresponding (S,S)-isomer(0.120 g, 23%), also as a white solid. (S,R)-isomer: ¹H NMR (CD₃OD) δ7.51-7.45 (m, 2H), 7.41-7.25 (m, 8H), 5.85 (q, J=6.6 Hz, 1H), 4.05 (s,1H), 2.56-2.45 (m, 2H), 2.41-2.29 (m, 2H), 1.71-1.49 (m, 4H), 1.38 (d,J=6.6 Hz, 3H), 1.18 (s, 3H). LC-MS: Anal. Calcd. for C₂₂H₂₇NO₃: 353.found: 354 (M+H)⁺. (S,S)-isomer: ¹H NMR (CD₃OD) δ 7.41-7.30 (m, 5H),7.20-7.14 (m, 3H), 7.06-7.00 (m, 2H), 5.85 (q, J=6.6 Hz, 1H), 4.06 (s,1H), 2.70-2.60 (m, 1H), 2.51 (dt, J=6.6, 3.3 Hz, 1H), 2.44-2.31 (m, 2H),1.75-1.65 (m, 1H), 1.65-1.54 (m, 3H), 1.50 (d, J=6.8 Hz, 3H), 1.20 (s,3H). LC-MS: Anal. Calcd. for C₂₂H₂₇NO₃: 353; found: 354 (M+H)⁺.

Step 3: (R)-2-(4-Hydroxy-4-methylpiperidin-1-yl)-2-phenylacetic acid. Toa solution of(S)-1-phenylethyl(R)-2-(4-hydroxy-4-methylpiperidin-1-yl)-2-phenylacetate(0.185 g, 0.52 mmol) in dichloromethane (3 mL) was added trifluoroaceticacid (1 mL) and the mixture was stirred at room temperature for 2 hours.The volatiles were subsequently removed in vacuo and the residue waspurified by reverse-phase preparative HPLC (Primesphere C-18, 20×100 mm;CH₃CN—H₂O-0.1% TFA) to give the title compound (as TFA salt) as a palebluish solid (0.128 g, 98%). LC-MS: Anal. Calcd. for C₁₄H₁₉NO₃: 249;found: 250 (M+H)⁺.

Cap-16

Step 1: (S)-1-Phenylethyl 2-(2-fluorophenyl)acetate. A mixture of2-fluorophenylacetic acid (5.45 g, 35.4 mmol), (S)-1-phenylethanol (5.62g, 46.0 mmol), EDCI (8.82 g, 46.0 mmol) and DMAP (0.561 g, 4.60 mmol) inCH₂Cl₂ (100 mL) was stirred at room temperature for 12 hours. Thesolvent was then concentrated and the residue partitioned with H₂O-ethylacetate. The phases were separated and the aqueous layer back-extractedwith ethyl acetate (2×). The combined organic phases were washed (H₂O,brine), dried (Na₂SO₄), filtered, and concentrated in vacuo. The residuewas purified by silica gel chromatography (BIOTAGE®/0-20% ethylacetate-hexane) to provide the title compound as a colorless oil (8.38g, 92%). ¹H NMR (400 MHz, CD₃OD) δ 7.32-7.23 (m, 7H), 7.10-7.04 (m, 2),5.85 (q, J=6.5 Hz, 1H), 3.71 (s, 2H), 1.48 (d, J=6.5 Hz, 3H).

Step 2: (R)—((S)-1-Phenylethyl)2-(2-fluorophenyl)-2-(piperidin-1-yl)acetate. To a solution of(S)-1-phenylethyl 2-(2-fluorophenyl)acetate (5.00 g, 19.4 mmol) in THF(1200 mL) at 0° C. was added DBU (6.19 g, 40.7 mmol) and the solutionwas allowed to warm to room temperature while stirring for 30 minutes.The solution was then cooled to −78° C. and a solution of CBr₄ (13.5 g,40.7 mmol) in THF (100 mL) was added and the mixture was allowed to warmto −10° C. and stirred at this temperature for 2 hours. The reactionmixture was quenched with saturated aq. NH₄Cl and the layers wereseparated. The aqueous layer was back-extracted with ethyl acetate (2×)and the combined organic phases were washed (H₂O, brine), dried(Na₂SO₄), filtered, and concentrated in vacuo. To the residue was addedpiperidine (5.73 mL, 58.1 mmol) and the solution was stirred at roomtemperature for 24 hours. The volatiles were then concentrated in vacuoand the residue was purified by silica gel chromatography(BIOTAGE®/0-30% diethyl ether-hexane) to provide a pure mixture ofdiastereomers (2:1 ratio by ¹H NMR) as a yellow oil (2.07 g, 31%), alongwith unreacted starting material (2.53 g, 51%). Further chromatographyof the diastereomeric mixture (BIOTAGE®/0-10% diethyl ether-toluene)provided the title compound as a colorless oil (0.737 g, 11%). ¹H NMR(400 MHz, CD₃OD) δ 7.52 (ddd, J=9.4, 7.6, 1.8 Hz, 1H), 7.33-7.40 (m, 1),7.23-7.23 (m, 4H), 7.02-7.23 (m, 4H), 5.86 (q, J=6.6 Hz, 1H), 4.45 (s,1H), 2.39-2.45 (m, 4H), 1.52-1.58 (m, 4H), 1.40-1.42 (m, 1H), 1.38 (d,J=6.6 Hz, 3H). LC-MS: Anal. Calcd. for C₂₁H₂₄FNO₂: 341; found: 342(M+H)⁺.

Step 3: (R)-2-(2-Fluorophenyl)-2-(piperidin-1-yl)acetic acid. A mixtureof (R)—((S)-1-phenylethyl) 2-(2-fluorophenyl)-2-(piperidin-1-yl)acetate(0.737 g, 2.16 mmol) and 20% Pd(OH)₂/C (0.070 g) in ethanol (30 mL) washydrogenated at room temperature and atmospheric pressure (H₂ balloon)for 2 hours. The solution was then purged with Ar, filtered throughdiatomaceous earth (CELITE®), and concentrated in vacuo. This providedthe title compound as a colorless solid (0.503 g, 98%). ¹H NMR (400 MHz,CD₃OD) δ 7.65 (ddd, J=9.1, 7.6, 1.5 Hz, 1H), 7.47-7.53 (m, 1H),7.21-7.30 (m, 2H), 3.07-3.13 (m, 4H), 1.84 (br s, 4H), 1.62 (br s, 2H).LC-MS: Anal. Calcd. for C₁₃H₁₆FNO₂: 237; found: 238 (M+H)⁺.

Cap-17

Step 1:(S)-1-Phenylethyl(R)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-2-phenylacetate.To a solution of (S)-1-phenylethyl 2-bromo-2-phenylacetate (1.50 g, 4.70mmol) in THF (25 mL) was added triethylamine (1.31 mL, 9.42 mmol),followed by tetrabutylammonium iodide (0.347 g, 0.94 mmol). The reactionmixture was stirred at room temperature for 5 minutes and then asolution of 4-phenyl-4-hydroxypiperidine (1.00 g, 5.64 mmol) in THF (5mL) was added. The mixture was stirred for 16 hours and then it wasdiluted with ethyl acetate (100 mL), washed (H₂O×2, brine), dried(MgSO₄), filtered and concentrated. The residue was purified on a silicagel column (0-60% ethyl acetate-hexane) to provide an approximately 2:1mixture of diastereomers, as judged by ¹H NMR. Separation of theseisomers was performed using supercritical fluid chromatography(CHIRALCEL® OJ-H, 30×250 mm; 20% ethanol in CO₂ at 35° C.), to givefirst the (R)-isomer of the title compound (0.534 g, 27%) as a yellowoil and then the corresponding (S)-isomer (0.271 g, 14%), also as ayellow oil. (S,R)-isomer: ¹H NMR (400 MHz, CD₃OD) δ 7.55-7.47 (m, 4H),7.44-7.25 (m, 10H), 7.25-7.17 (m, 1H), 5.88 (q, J=6.6 Hz, 1H), 4.12 (s,1H), 2.82-2.72 (m, 1H), 2.64 (dt, J=11.1, 2.5 Hz, 1H), 2.58-2.52 (m,1H), 2.40 (dt, J=11.1, 2.5 Hz, 1H), 2.20 (dt, J=12.1, 4.6 Hz, 1H), 2.10(dt, J=12.1, 4.6 Hz, 1H), 1.72-1.57 (m, 2H), 1.53 (d, J=6.5 Hz, 3H).LC-MS: Anal. Calcd. for C₂₇H₂₉NO₃: 415; found: 416 (M+H)⁺; (S,S)-isomer:H¹NMR (400 MHz, CD₃OD) δ 7.55-7.48 (m, 2H), 7.45-7.39 (m, 2H), 7.38-7.30(m, 5H), 7.25-7.13 (m, 4H), 7.08-7.00 (m, 2H), 5.88 (q, J=6.6 Hz, 1H),4.12 (s, 1H), 2.95-2.85 (m, 1H), 2.68 (dt, J=11.1, 2.5 Hz, 1H),2.57-2.52 (m, 1H), 2.42 (dt, J=11.1, 2.5 Hz, 1H), 2.25 (dt, J=12.1, 4.6Hz, 1H), 2.12 (dt, J=12.1, 4.6 Hz, 1H), 1.73 (dd, J=13.6, 3.0 Hz, 1H),1.64 (dd, J=13.6, 3.0 Hz, 1H), 1.40 (d, J=6.6 Hz, 3H). LC-MS: Anal.Calcd. for C₂₂H₂₉NO₃: 415; found: 416 (M+H)⁺.

The following esters were prepared in similar fashion:

Intermediate-17a

Diastereomer 1: ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.36 (d, J = 6.41 Hz,3H) 2.23-2.51 (m, 4H) 3.35 (s, 4H) 4.25 (s, 1H) 5.05 (s, 2H) 5.82 (d, J= 6.71 Hz, 1H) 7.15-7.52 (m, 15H). LC-MS: Anal. Calcd. for: C₂₈H₃₀N₂O₄458.22; found: 459.44 (M + H)⁺. Diastereomer 2: ¹H NMR (500 MHz,DMSO-d₆) δ ppm 1.45 (d, J = 6.71 Hz, 3H) 2.27-2.44 (m, 4H) 3.39 (s, 4H)4.23 (s, 1H) 5.06 (s, 2H) 5.83 (d, J = 6.71 Hz, 1H) 7.12 (dd, J = 6.41,3.05 Hz, 2H) 7.19-7.27 (m, 3H) 7.27-7.44 (m, 10H). LC-MS: Anal. Calcd.for: C₂₈H₃₀N₂O₄ 458.22; found: 459.44 (M + H)⁺. Intermediate-17b

Diastereomer 1: RT = 11.76 minutes (Condition II); LC-MS: Anal. Calcd.for: C₂₀N₂₂N₂O₃ 338.16; found: 339.39 (M + H)⁺. Diastereomer 2: RT =10.05 minutes (Condition II). LC-MS: Anal. Calcd. for: C₂₀N₂₂N₂O₃338.16; found: 339.39 (M + H)⁺. Intermediate-17c

Diastereomer 1: T_(R) = 4.55 minutes (Condition I); LC-MS: Anal. Calcd.for: C₂₁H₂₆N₂O₂ 338.20; found: 339.45 (M + H)⁺. Diastereomer 2: T_(R) =6.00 minutes (Condition I). LC-MS: Anal. Calcd. for: C₂₁H₂₆N₂O₂ 338.20;found: 339.45 (M + H)⁺. Intermediate-17d

Diastereomer 1: RT = 7.19 minutes (Condition I); LC-MS: Anal. Calcd.for: C₂₇H₂₉NO₂ 399.22; found: 400.48 (M + H)⁺. Diastereomer 2: RT = 9.76minutes (Condition I); LC-MS: Anal. Calcd. for: C₂₇H₂₉NO₂ 399.22; found:400.48 (M + H)⁺.Chiral SFC Conditions for Determining Retention Time:Condition I

-   Column: CHIRALPAK® AD-H Column, 4.62×50 mm, 5 μm-   Solvents: 90% CO₂-10% methanol with 0.1% DEA-   Temp: 35° C.-   Pressure: 150 bar-   Flow rate: 2.0 mL/min.-   UV monitored at 220 nm-   Injection: 1.0 mg/3 mL methanol    Condition II-   Column: CHIRALCEL® OD-H Column, 4.62×50 mm, 5 μm-   Solvents: 90% CO₂-10% methanol with 0.1% DEA-   Temp: 35° C.-   Pressure: 150 bar-   Flow rate: 2.0 mL/min.-   UV monitored at 220 nm-   Injection: 1.0 mg/mL methanol

Cap-17, Step 2: (R)-2-(4-Hydroxy-4-phenylpiperidin-1-yl)-2-phenylaceticacid. To a solution of(S)-1-phenylethyl(R)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-2-phenylacetate(0.350 g, 0.84 mmol) in dichloromethane (5 mL) was added trifluoroaceticacid (1 mL) and the mixture was stirred at room temperature for 2 hours.The volatiles were subsequently removed in vacuo and the residue waspurified by reverse-phase preparative HPLC (Primesphere C-18, 20×100 mm;CH₃CN—H₂O-0.1% TFA) to give the title compound (as TFA salt) as a whitesolid (0.230 g, 88%). LC-MS: Anal. Calcd. for C₁₉H₂₁NO₃: 311.15; found:312 (M+H)⁺.

The following carboxylic acids were prepared in optically pure form in asimilar fashion:

Cap-17a

RT = 2.21 (Condition II); ¹H NMR (500 MHz, DMSO-d₆) δ ppm 2.20-2.35 (m,2H) 2.34-2.47 (m, 2H) 3.37 (s, 4H) 3.71 (s, 1H) 5.06 (s, 2H) 7.06-7.53(m, 10H). LC-MS: Anal. Calcd. for: C₂₀N₂₂N₂O₄ 354.16; found: 355.38 (M +H)⁺. Cap-17b

RT = 0.27 (Condition III); LC-MS: Anal. Calcd. for: C₁₂H₁₄N₂O₃ 234.10;found: 235.22 (M + H)⁺. Cap-17c

RT = 0.48 (Condition II); LC-MS: Anal. Calcd. for: C₁₃H₁₈N₂O₂ 234.14;found: 235.31 (M + H)⁺. Cap-17d

RT = 2.21 (Condition I); LC-MS: Anal. Calcd. for: C₁₉H₂₁NO₂ 295.16;found: 296.33 (M + H)⁺.LC-MS Conditions for Determining Retention Time:Condition I

-   Column: PHENOMENEX® Luna 4.6×50 mm S10-   Start % B=0-   Final % B=100-   Gradient Time=4 min-   Flow Rate=4 mL/min-   Wavelength=220-   Solvent A=10% methanol—90% H₂O—0.1% TFA-   Solvent B=90% methanol—10% H₂O—0.1% TFA    Condition II-   Column: Waters SunFire 4.6×50 mm S5-   Start % B=0-   Final % B=100-   Gradient Time=2 min-   Flow Rate=4 mL/min-   Wavelength=220-   Solvent A=10% methanol—90% H₂O—0.1% TFA-   Solvent B=90% methanol—10% H₂O—0.1% TFA    Condition III-   Column: PHENOMENEX® 10μ3.0×50 mm-   Start % B=0-   Final % B=100-   Gradient Time=2 min-   Flow Rate=4 mL/min-   Wavelength=220-   Solvent A=10% methanol—90% H₂O—0.1% TFA-   Solvent B=90% methanol—10% H₂O—0.1% TFA

Cap-18

Step 1: (R,S)-Ethyl 2-(4-pyridyl)-2-bromoacetate. To a solution of ethyl4-pyridylacetate (1.00 g, 6.05 mmol) in dry THF (150 mL) at 0° C. underargon was added DBU (0.99 mL, 6.66 mmol). The reaction mixture wasallowed to warm to room temperature over 30 minutes and then it wascooled to −78° C. To this mixture was added CBr₄ (2.21 g, 6.66 mmol) andstirring was continued at −78° C. for 2 hours. The reaction mixture wasthen quenched with sat. aq. NH₄Cl and the phases were separated. Theorganic phase was washed (brine), dried (Na₂SO₄), filtered, andconcentrated in vacuo. The resulting yellow oil was immediately purifiedby flash chromatography (SiO₂/hexane-ethyl acetate, 1:1) to provide thetitle compound (1.40 g, 95%) as a somewhat unstable yellow oil. ¹H NMR(400 MHz, CDCl₃) δ 8.62 (dd, J=4.6, 1.8 Hz, 2H), 7.45 (dd, J=4.6, 1.8Hz, 2H), 5.24 (s, 1H), 4.21-4.29 (m, 2H), 1.28 (t, J=7.1 Hz, 3H). LC-MS:Anal. Calcd. for C₉H₁₀BrNO₂: 242, 244; found: 243, 245 (M+H)⁺.

Step 2: (R,S)-Ethyl 2-(4-pyridyl)-2-(N,N-dimethylamino)acetate. To asolution of (R,S)-ethyl 2-(4-pyridyl)-2-bromoacetate (1.40 g, 8.48 mmol)in DMF (10 mL) at room temperature was added dimethylamine (2M in THF,8.5 mL, 17.0 mmol). After completion of the reaction (as judged by thinlayer chromatography) the volatiles were removed in vacuo and theresidue was purified by flash chromatography (BIOTAGE®, 40+M SiO₂column; 50%-100% ethyl acetate-hexane) to provide the title compound(0.539 g, 31%) as a light yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 8.58 (d,J=6.0 Hz, 2H), 7.36 (d, J=6.0 Hz, 2H), 4.17 (m, 2H), 3.92 (s, 1H), 2.27(s, 6H), 1.22 (t, J=7.0 Hz). LC-MS: Anal. Calcd. for C₁₁H₁₆N₂O₂: 208;found: 209 (M+H)⁺.

Step 3: (R,S)-2-(4-Pyridyl)-2-(N,N-dimethylamino)acetic acid. To asolution of (R,S)-ethyl 2-(4-pyridyl)-2-(N,N-dimethylamino)acetate(0.200 g, 0.960 mmol) in a mixture of THF-methanol-H₂O (1:1:1, 6 mL) wasadded powdered LiOH (0.120 g, 4.99 mmol) at room temperature. Thesolution was stirred for 3 hours and then it was acidified to pH 6 using1N HCl. The aqueous phase was washed with ethyl acetate and then it waslyophilized to give the dihydrochloride of the title compound as ayellow solid (containing LiCl). The product was used as such insubsequent steps. ¹H NMR (400 MHz, DMSO-d₆) δ 8.49 (d, J=5.7 Hz, 2H),7.34 (d, J=5.7 Hz, 2H), 3.56 (s, 1H), 2.21 (s, 6H).

The following examples were prepared in similar fashion using the methoddescribed above:

Cap-19

LC-MS: Anal. Calcd. for C₉H₁₂N₂O₂ : 180; found: 181 (M + H)⁺. Cap-20

LC-MS: no ionization. ¹H NMR (400 MHz, CD₃OD) δ 8.55 (d, J = 4.3 Hz,1H), 7.84 (app t, J = 5.3 Hz, 1H), 7.61 (d, J = 7.8 Hz, 1H), 7.37 (appt, J = 5.3 Hz, 1H), 4.35 (s, 1H), 2.60 (s, 6H). Cap-21

LC-MS: Anal. Calcd. for C₉H₁₁ClN₂O₂: 214, 216; found: 215, 217 (M + H)⁺.Cap-22

LC-MS: Anal. Calcd. for C₁₀H₁₂N₂O₄: 224; found: 225 (M + H)⁺. Cap-23

LC-MS: Anal. Calcd. for C₁₄H₁₅NO₂: 229; found: 230 (M + H)⁺. Cap-24

LC-MS: Anal. Calcd. for C₁₁H₁₂F₃NO₂: 247; found: 248 (M + H)⁺. Cap-25

LC-MS: Anal. Calcd. for C₁₁H₁₂F₃NO₂: 247; found: 248 (M + H)⁺. Cap-26

LC-MS: Anal. Calcd. for C₁₀H₁₂FNO₂: 197; found: 198 (M + H)⁺. Cap-27

LC-MS: Anal. Calcd. for C₁₀H₁₂FNO₂: 247; found: 248 (M + H)⁺. Cap-28

LC-MS: Anal. Calcd. for C₁₀H₁₂ClNO₂: 213; found: 214 (M + H)⁺. Cap-29

LC-MS: Anal. Calcd. for C₁₀H₁₂ClNO₂: 213; found: 214 (M + H)⁺. Cap-30

LC-MS: Anal. Calcd. for C₁₀H₁₂ClNO₂: 213; found: 214 (M + H)⁺. Cap-31

LC-MS: Anal. Calcd. for C₈H₁₂N₂O₂S: 200; found: 201 (M + H)⁺. Cap-32

LC-MS: Anal. Calcd. for C₈H₁₁NO₂S: 185; found: 186 (M + H)⁺. Cap-33

LC-MS: Anal. Calcd. for C₈H₁₁NO₂S: 185; found: 186 (M + H)⁺. Cap-34

LC-MS: Anal. Calcd. for C₁₁H₁₂N₂O₃: 220; found: 221 (M + H)⁺. Cap-35

LC-MS: Anal. Calcd. for C₁₂H₁₃NO₂S: 235; found: 236 (M + H)⁺. Cap-36

LC-MS: Anal. Calcd. for C₁₂H₁₄N₂O₂S: 250; found: 251 (M + H)⁺.

Cap-37

Step 1: (R,S)-Ethyl 2-(quinolin-3-yl)-2-(N,N-dimethylamino)-acetate. Amixture of ethyl N,N-dimethylaminoacetate (0.462 g, 3.54 mmol), K₃PO₄(1.90 g, 8.95 mmol), Pd(t-Bu₃P)₂ (0.090 g, 0.176 mmol), 3-bromoquinolineand toluene (10 mL) was degassed with a stream of Ar bubbles for 15minutes. The reaction mixture was then heated at 100° C. for 12 hours,after which it was cooled to room temperature and poured into H₂O. Themixture was extracted with ethyl acetate (2×) and the combined organicphases were washed (H₂O, brine), dried (Na₂SO₄), filtered, andconcentrated in vacuo. The residue was purified first by reverse-phasepreparative HPLC (Primesphere C-18, 30×100 mm; CH₃CN—H₂O-5 mM NH₄OAc)and then by flash chromatography (SiO₂/hexane-ethyl acetate, 1:1) toprovide the title compound (0.128 g, 17%) as an orange oil. ¹H NMR (400MHz, CDCl₃) δ 8.90 (d, J=2.0 Hz, 1H), 8.32 (d, J=2.0 Hz, 1H), 8.03-8.01(m, 2H), 7.77 (ddd, J=8.3, 6.8, 1.5 Hz, 1H), 7.62 (ddd, J=8.3, 6.8, 1.5Hz, 1H), 4.35 (s, 1H), 4.13 (m, 2H), 2.22 (s, 6H), 1.15 (t, J=7.0 Hz,3H). LC-MS: Anal. Calcd. for C₁₅H₁₈N₂O₂: 258; found: 259 (M+H)⁺.

Step 2: (R,S) 2-(Quinolin-3-yl)-2-(N,N-dimethylamino)acetic acid. Amixture of (R,S)-ethyl 2-(quinolin-3-yl)-2-(N,N-dimethylamino)acetate(0.122 g, 0.472 mmol) and 6M HCl (3 mL) was heated at 100° C. for 12hours. The solvent was removed in vacuo to provide the dihydrochlorideof the title compound (0.169 g, >100%) as a light yellow foam. Theunpurified material was used in subsequent steps without furtherpurification. LC-MS: Anal. Calcd. for C₁₃H₁₄N₂O₂: 230; found: 231(M+H)⁺.

Cap-38

Step 1: (R)—((S)-1-Phenylethyl)2-(dimethylamino)-2-(2-fluorophenyl)acetate and (S)—((S)-1-Phenylethyl)2-(dimethylamino)-2-(2-fluorophenyl)acetate. To a mixture of(RS)-2-(dimethylamino)-2-(2-fluorophenyl)acetic acid (2.60 g, 13.19mmol), DMAP (0.209 g, 1.71 mmol) and (S)-1-phenylethanol (2.09 g, 17.15mmol) in CH₂Cl₂ (40 mL) was added EDCI (3.29 g, 17.15 mmol) and themixture was allowed to stir at room temperature for 12 hours. Thesolvent was then removed in vacuo and the residue partitioned with ethylacetate-H₂O. The layers were separated, the aqueous layer wasback-extracted with ethyl acetate (2×) and the combined organic phaseswere washed (H₂O, brine), dried (Na₂SO₄), filtered, and concentrated invacuo. The residue was purified by silica gel chromatography(BIOTAGE®/0-50% diethyl ether-hexane). The resulting pure diastereomericmixture was then separated by reverse-phase preparative HPLC(Primesphere C-18, 30×100 mm; CH₃CN—H₂O-0.1% TFA) to give first(S)-1-phenethyl(R)-2-(dimethylamino)-2-(2-fluorophenyl)acetate (0.501 g,13%) and then(S)-1-phenethyl(S)-2-(dimethylamino)-2-(2-fluorophenyl)-acetate (0.727g. 18%), both as their TFA salts. (S,R)-isomer: ¹H NMR (400 MHz, CD₃OD)δ 7.65-7.70 (m, 1H), 7.55-7.60 (ddd, J=9.4, 8.1, 1.5 Hz, 1H), 7.36-7.41(m, 2H), 7.28-7.34 (m, 5H), 6.04 (q, J=6.5 Hz, 1H), 5.60 (s, 1H), 2.84(s, 6H), 1.43 (d, J=6.5 Hz, 3H). LC-MS: Anal. Calcd. for C₁₈H₂₀FNO₂:301; found: 302 (M+H)⁺; (S,S)-isomer: ¹H NMR (400 MHz, CD₃OD) δ7.58-7.63 (m, 1H), 7.18-7.31 (m, 6H), 7.00 (dd, J=8.5, 1.5 Hz, 2H), 6.02(q, J=6.5 Hz, 1H), 5.60 (s, 1H), 2.88 (s, 6H), 1.54 (d, J=6.5 Hz, 3H).LC-MS: Anal. Calcd. for C₁₈H₂₀FNO₂: 301; found: 302 (M+H)⁺.

Step 2: (R)-2-(Dimethylamino)-2-(2-fluorophenyl)acetic acid. A mixtureof (R)—((S)-1-phenylethyl) 2-(dimethylamino)-2-(2-fluorophenyl)acetateTFA salt (1.25 g, 3.01 mmol) and 20% Pd(OH)₂/C (0.125 g) in ethanol (30mL) was hydrogenated at room temperature and atmospheric pressure (H₂balloon) for 4 hours. The solution was then purged with Ar, filteredthrough diatomaceous earth (CELITE®), and concentrated in vacuo. Thisgave the title compound as a colorless solid (0.503 g, 98%). ¹H NMR (400MHz, CD₃OD) δ 7.53-7.63 (m, 2H), 7.33-7.38 (m, 2H), 5.36 (s, 1H), 2.86(s, 6H). LC-MS: Anal. Calcd. for C₁₀H₁₂FNO₂: 197; found: 198 (M+H)⁺.

The S-isomer could be obtained from (S)—((S)-1-phenylethyl)2-(dimethylamino)-2-(2-fluorophenyl)acetate TFA salt in similar fashion.

Cap-39

A mixture of (R)-(2-chlorophenyl)glycine (0.300 g, 1.62 mmol),formaldehyde (35% aqueous solution, 0.80 mL, 3.23 mmol) and 20%Pd(OH)₂/C (0.050 g) was hydrogenated at room temperature and atmosphericpressure (H₂ balloon) for 4 hours. The solution was then purged with Ar,filtered through diatomaceous earth (CELITE®) and concentrated in vacuo.The residue was purified by reverse-phase preparative HPLC (PrimesphereC-18, 30×100 mm; CH₃CN—H₂O-0.1% TFA) to give the TFA salt of the titlecompound (R)-2-(dimethylamino)-2-(2-chlorophenyl)acetic acid as acolorless oil (0.290 g, 55%). ¹H NMR (400 MHz, CD₃OD) δ 7.59-7.65 (m,2H), 7.45-7.53 (m, 2H), 5.40 (s, 1H), 2.87 (s, 6H). LC-MS: Anal. Calcd.for C₁₀H₁₂ClNO₂: 213; found: 214 (M+H)⁺.

Cap-40

To an ice-cold solution of (R)-(2-chlorophenyl)glycine (1.00 g, 5.38mmol) and NaOH (0.862 g, 21.6 mmol) in H₂O (5.5 mL) was added methylchloroformate (1.00 mL, 13.5 mmol) dropwise. The mixture was allowed tostir at 0° C. for 1 hour and then it was acidified by the addition ofconc. HCl (2.5 mL). The mixture was extracted with ethyl acetate (2×)and the combined organic phase was washed (H₂O, brine), dried (Na₂SO₄),filtered, and concentrated in vacuo to give the title compound(R)-2-(methoxycarbonylamino)-2-(2-chlorophenyl)acetic acid as ayellow-orange foam (1.31 g, 96%). ¹H NMR (400 MHz, CD₃OD) δ 7.39-7.43(m, 2H), 7.29-7.31 (m, 2H), 5.69 (s, 1H), 3.65 (s, 3H). LC-MS: Anal.Calcd. for C₁₀H₁₀ClNO₄: 243; found: 244 (M+H)⁺.

Cap-41

To a suspension of 2-(2-(chloromethyl)phenyl)acetic acid (2.00 g, 10.8mmol) in THF (20 mL) was added morpholine (1.89 g, 21.7 mmol) and thesolution was stirred at room temperature for 3 hours. The reactionmixture was then diluted with ethyl acetate and extracted with H₂O (2×).The aqueous phase was lyophilized and the residue was purified by silicagel chromatography (BIOTAGE®/0-10% methanol-CH₂Cl₂) to give the titlecompound 2-(2-(morpholinomethyl)phenyl)acetic acid as a colorless solid(2.22 g, 87%). ¹H NMR (400 MHz, CD₃OD) δ 7.37-7.44 (m, 3H), 7.29-7.33(m, 1H), 4.24 (s, 2H), 3.83 (br s, 4H), 3.68 (s, 2H), 3.14 (br s, 4H).LC-MS: Anal. Calcd. for C₁₃H₁₇NO₃: 235; found: 236 (M+H)⁺.

The following examples were similarly prepared using the methoddescribed for Cap-41:

Cap-42

LC-MS: Anal. Calcd. for C₁₄H₁₉NO₂: 233; found: 234 (M + H)⁺. Cap-43

LC-MS: Anal. Calcd. for C₁₃H₁₇NO₂: 219; found: 220 (M + H)⁺. Cap-44

LC-MS: Anal. Calcd. for C₁₁H₁₅NO₂: 193; found: 194 (M + H)⁺. Cap-45

LC-MS: Anal. Calcd. for C₁₄H₂₀N₂O₂: 248; found: 249 (M + H)⁺.

Cap-45a

HMDS (1.85 mL, 8.77 mmol) was added to a suspension of(R)-2-amino-2-phenylacetic acid p-toluenesulfonate (2.83 g, 8.77 mmol)in CH₂Cl₂ (10 mL) and the mixture was stirred at room temperature for 30minutes. Methyl isocyanate (0.5 g, 8.77 mmol) was added in one portionstirring continued for 30 minutes. The reaction was quenched by additionof H₂O (5 mL) and the resulting precipitate was filtered, washed withH₂O and n-hexanes, and dried under vacuum.(R)-2-(3-methylureido)-2-phenylacetic acid (1.5 g; 82%) was recovered asa white solid and it was used without further purification. ¹H NMR (500MHz, DMSO-d₆) δ ppm 2.54 (d, J=4.88 Hz, 3H) 5.17 (d, J=7.93 Hz, 1H) 5.95(q, J=4.48 Hz, 1H) 6.66 (d, J=7.93 Hz, 1H) 7.26-7.38 (m, 5H) 12.67 (s,1H). LC-MS: Anal. Calcd. for C₁₀H₁₂N₂O₃ 208.08 found 209.121 (M+H)⁺;HPLC PHENOMENEX® C-18 3.0×46 mm, 0 to 100% B over 2 minutes, 1 minutehold time, A=90% water, 10% methanol, 0.1% TFA, B=10% water, 90%methanol, 0.1% TFA, RT=1.38 min, 90% homogeneity index.

Cap-46

The desired product was prepared according to the method described forCap-45a. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.96 (t, J=7.17 Hz, 3H)2.94-3.05 (m, 2H) 5.17 (d, J=7.93 Hz, 1H) 6.05 (t, J=5.19 Hz, 1H) 6.60(d, J=7.63 Hz, 1H) 7.26-7.38 (m, 5H) 12.68 (s, 1H). LC-MS: Anal. Calcd.for C₁₁H₁₄N₂O₃ 222.10 found 223.15 (M+H)⁺. HPLC XTERRA® C-18 3.0×506 mm,0 to 100% B over 2 minutes, 1 minute hold time, A=90% water, 10%methanol, 0.2% H₃PO₄, B=10% water, 90% methanol, 0.2% H₃PO₄, RT=0.87min, 90% homogeneity index.

Cap-47

Step 1: (R)-tert-Butyl 2-(3,3-dimethylureido)-2-phenylacetate. To astirred solution of (R)-tert-butyl-2-amino-2-phenylacetate (1.0 g, 4.10mmol) and Hunig's base (1.79 mL, 10.25 mmol) in DMF (40 mL) was addeddimethylcarbamoyl chloride (0.38 mL, 4.18 mmol) dropwise over 10minutes. After stirring at room temperature for 3 hours, the reactionwas concentrated under reduced pressure and the resulting residue wasdissolved in ethyl acetate. The organic layer was washed with H₂O, 1Naq. HCl and brine, dried (MgSO₄), filtered and concentrated underreduced pressure. (R)-tert-butyl 2-(3,3-dimethylureido)-2-phenylacetatewas obtained as a white solid (0.86 g; 75%) and used without furtherpurification. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.33 (s, 9H) 2.82 (s, 6H)5.17 (d, J=7.63 Hz, 1H) 6.55 (d, J=7.32 Hz, 1H) 7.24-7.41 (m, 5H).LC-MS: Anal. Calcd. for C₁₅H₂₂N₂O₃ 278.16 found 279.23 (M+H)⁺; HPLCPHENOMENEX® Luna C-18 4.6×50 mm, 0 to 100% B over 4 minutes, 1 minutehold time, A=90% water, 10% methanol, 0.1% TFA, B=10% water, 90%methanol, 0.1% TFA, RT=2.26 min, 97% homogeneity index.

Step 2: (R)-2-(3,3-Dimethylureido)-2-phenylacetic acid. To a stirredsolution of ((R)-tert-butyl 2-(3,3-dimethylureido)-2-phenylacetate (0.86g, 3.10 mmol) in CH₂Cl₂ (250 mL) was added TFA (15 mL) dropwise and theresulting solution was stirred at rt for 3 hours. The desired compoundwas then precipitated out of solution with a mixture of EtOAC:Hexanes(5:20), filtered off and dried under reduced pressure.(R)-2-(3,3-dimethylureido)-2-phenylacetic acid was isolated as a whitesolid (0.59 g, 86%) and used without further purification. ¹H NMR (500MHz, DMSO-d₆) δ ppm 2.82 (s, 6H) 5.22 (d, J=7.32 Hz, 1H) 6.58 (d, J=7.32Hz, 1H) 7.28 (t, J=7.17 Hz, 1H) 7.33 (t, J=7.32 Hz, 2H) 7.38-7.43 (m,2H) 12.65 (s, 1H). LC-MS: Anal. Calcd. for C₁₁H₁₄N₂O₃: 222.24; found:223.21 (M+H)⁺. HPLC XTERRA® C-18 3.0×50 mm, 0 to 100% B over 2 minutes,1 minute hold time, A=90% water, 10% methanol, 0.2% H₃PO₄, B=10% water,90% methanol, 0.2% H₃PO₄, RT=0.75 min, 93% homogeneity index.

Cap-48

Step 1: (R)-tert-Butyl 2-(3-cyclopentylureido)-2-phenylacetate. To astirred solution of (R)-2-amino-2-phenylacetic acid hydrochloride (1.0g, 4.10 mmol) and Hunig's base (1.0 mL, 6.15 mmol) in DMF (15 mL) wasadded cyclopentyl isocyanate (0.46 mL, 4.10 mmol) dropwise and over 10minutes. After stirring at room temperature for 3 hours, the reactionwas concentrated under reduced pressure and the resulting residue wastaken up in ethyl acetate. The organic layer was washed with H₂O andbrine, dried (MgSO₄), filtered, and concentrated under reduced pressure.(R)-tert-butyl 2-(3-cyclopentylureido)-2-phenylacetate was obtained asan opaque oil (1.32 g; 100%) and used without further purification. ¹HNMR (500 MHz, CD₃Cl-D) δ ppm 1.50-1.57 (m, 2H) 1.58-1.66 (m, 2H)1.87-1.97 (m, 2H) 3.89-3.98 (m, 1H) 5.37 (s, 1H) 7.26-7.38 (m, 5H).LC-MS: Anal. Calcd. for C₁₈H₂₆N₂O₃ 318.19 found 319.21 (M+H)⁺; HPLCXTERRA® C-18 3.0×50 mm, 0 to 100% B over 4 minutes, 1 minute hold time,A=90% water, 10% methanol, 0.1% TFA, B=10% water, 90% methanol, 0.1%TFA, RT=2.82 min, 96% homogeneity index.

Step 2: (R)-2-(3-Cyclopentylureido)-2-phenylacetic acid. To a stirredsolution of (R)-tert-butyl 2-(3-cyclopentylureido)-2-phenylacetate (1.31g, 4.10 mmol) in CH₂Cl₂ (25 mL) was added TFA (4 mL) and triethylsilane(1.64 mL; 10.3 mmol) dropwise, and the resulting solution was stirred atroom temperature for 6 hours. The volatile components were removed underreduced pressure and the crude product was recrystallized in ethylacetate/pentanes to yield (R)-2-(3-cyclopentylureido)-2-phenylaceticacid as a white solid (0.69 g, 64%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm1.17-1.35 (m, 2H) 1.42-1.52 (m, 2H) 1.53-1.64 (m, 2H) 1.67-1.80 (m, 2H)3.75-3.89 (m, 1H) 5.17 (d, J=7.93 Hz, 1H) 6.12 (d, J=7.32 Hz, 1H) 6.48(d, J=7.93 Hz, 1H) 7.24-7.40 (m, 5H) 12.73 (s, 1H). LC-MS: Anal. Calcd.for C₁₄H₁₈N₂O₃: 262.31; found: 263.15 (M+H)⁺. HPLC XTERRA® C-18 3.0×50mm, 0 to 100% B over 2 minutes, 1 minute hold time, A=90% water, 10%methanol, 0.2% H₃PO₄, B=10% water, 90% methanol, 0.2% H₃PO₄, RT=1.24min, 100% homogeneity index.

Cap-49

To a stirred solution of 2-(benzylamino)acetic acid (2.0 g, 12.1 mmol)in formic acid (91 mL) was added formaldehyde (6.94 mL, 93.2 mmol).After five hours at 70° C., the reaction mixture was concentrated underreduced pressure to 20 mL and a white solid precipitated. Followingfiltration, the mother liquors were collected and further concentratedunder reduced pressure providing the crude product. Purification byreverse-phase preparative HPLC (XTERRA® 30×100 mm, detection at 220 nm,flow rate 35 mL/min, 0 to 35% B over 8 min; A=90% water, 10% methanol,0.1% TFA, B=10% water, 90% methanol, 0.1% TFA) provided the titlecompound 2-(benzyl(methyl)-amino)acetic acid as its TFA salt (723 mg,33%) as a colorless wax. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.75 (s, 3H)4.04 (s, 2H) 4.34 (s, 2H) 7.29-7.68 (m, 5H). LC-MS: Anal. Calcd. for:C₁₀H₁₃NO₂ 179.09; found: 180.20 (M+H)⁺.

Cap-50

To a stirred solution of 3-methyl-2-(methylamino)butanoic acid (0.50 g,3.81 mmol) in water (30 mL) was added K₂CO₃ (2.63 g, 19.1 mmol) andbenzyl chloride (1.32 g, 11.4 mmol). The reaction mixture was stirred atambient temperature for 18 hours. The reaction mixture was extractedwith ethyl acetate (30 mL×2) and the aqueous layer was concentratedunder reduced pressure providing the crude product which was purified byreverse-phase preparative HPLC (XTERRA® 30×100 mm, detection at 220 nm,flow rate 40 mL/min, 20 to 80% B over 6 min; A=90% water, 10% methanol,0.1% TFA, B=10% water, 90% methanol, 0.1% TFA) to provide2-(benzyl(methyl)amino)-3-methylbutanoic acid, TFA salt (126 mg, 19%) asa colorless wax. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.98 (d, 3H) 1.07 (d,3H) 2.33-2.48 (m, 1H) 2.54-2.78 (m, 3H) 3.69 (s, 1H) 4.24 (s, 2H)7.29-7.65 (m, 5H). LC-MS: Anal. Calcd. for: C₁₃H₁₉NO₂ 221.14; found:222.28 (M+H)⁺.

Cap-51

(S)-2-(Methoxycarbonylamino)-3-methylbutanoic acid

Na₂CO₃ (1.83 g, 17.2 mmol) was added to NaOH (33 mL of 1M/H₂O, 33 mmol)solution of L-valine (3.9 g, 33.29 mmol) and the resulting solution wascooled with ice-water bath. Methyl chloroformate (2.8 mL, 36.1 mmol) wasadded dropwise over 15 min, the cooling bath was removed and thereaction mixture was stirred at ambient temperature for 3.25 hr. Thereaction mixture was washed with ether (50 mL, 3×), and the aqueousphase was cooled with ice-water bath and acidified with concentrated HClto a pH region of 1-2, and extracted with CH₂Cl₂ (50 mL, 3×). Theorganic phase was dried (MgSO₄) and evaporated in vacuo to afford Cap-51as a white solid (6 g). ¹H NMR for the dominant rotamer (DMSO-d₆, δ=2.5ppm, 500 MHz): 12.54 (s, 1H), 7.33 (d, J=8.6, 1H), 3.84 (dd, J=8.4, 6.0,1H), 3.54 (s, 3H), 2.03 (m, 1H), 0.87 (m, 6H). HRMS: Anal. Calcd. for[M+H]⁺ C₇H₁₄NO₄: 176.0923; found 176.0922.

Cap-51 (Alternate Route)

(S)-2-(Methoxycarbonylamino)-3-methylbutanoic acid

DIEA (137.5 mL, 0.766 mol) was added to a suspension of (S)-tert-butyl2-amino-3-methylbutanoate hydrochloride (75.0 g, 0.357 mol) in THF (900mL), and the mixture was cooled to 0° C. (ice/water bath). Methylchloroformate (29.0 mL, 0.375 mol) was added dropwise over 45 min, thecooling bath was removed and the heterogeneous mixture was stirred atambient temperature for 3 h. The solvent was removed under diminishedpressure and the residue partitioned between EtOAc and water (1 L each).The organic layer was washed with H₂O (1 L) and brine (1 L), dried(MgSO₄), filtered and concentrated under diminished pressure. The crudematerial was passed through a plug of silica gel (1 kg), eluting withhexanes (4 L) and 15:85 EtOAc/hexanes (4 L) to afford (S)-tert-butyl2-(methoxycarbonylamino)-3-methylbutanoate as a clear oil (82.0 g, 99%yield). ¹H NMR (500 MHz, DMSO-d₆, δ=2.5 ppm) 7.34 (d, J=8.6, 1 H), 3.77(dd, J=8.6, 6.1, 1 H), 3.53 (s, 3 H), 1.94-2.05 (m, 1 H), 1.39 (s, 9 H),0.83-0.92 (m, 6 H). ¹³C-NMR (126 MHz, DMSO-d₆, δ=39.2 ppm) 170.92,156.84, 80.38, 60.00, 51.34, 29.76, 27.62, 18.92, 17.95. LC-MS:[M+Na]⁺254.17.

Trifluoroacetic acid (343 mL, 4.62 mol) and Et₃SiH (142 mL, 0.887 mol)were added sequentially to a solution of (S)-tert-butyl2-(methoxycarbonylamino)-3-methylbutanoate (82.0 g, 0.355 mol) in CH₂Cl₂(675 mL), and the mixture was stirred at ambient temperature for 4 h.The volatile component was removed under diminished pressure and theresultant oil triturated with petroleum ether (600 mL) to afford a whitesolid, which was filtered and washed with hexanes (500 mL) and petroleumether (500 mL). Recrystallization from EtOAc/petroleum ether affordedCap-51 as white flaky crystals (54.8 g, 88% yield). MP=108.5-109.5° C.¹H NMR (500 MHz, DMSO-d₆, δ=2.5 ppm) 12.52 (s, 1 H), 7.31 (d, J=8.6, 1H), 3.83 (dd, J=8.6, 6.1, 1 H), 3.53 (s, 3 H), 1.94-2.07 (m, 1 H), 0.86(dd, J=8.9, 7.0, 6 H). ¹³C NMR (126 MHz, DMSO-d₆, δ=39.2 ppm) 173.30,156.94, 59.48, 51.37, 29.52, 19.15, 17.98. LC-MS: [M+H]⁺=176.11. Anal.Calcd. for C₇H₁₃NO₄: C, 47.99; H, 7.48; N, 7.99. Found: C, 48.17; H,7.55; N, 7.99. Optical Rotation: [α]_(D)=−4.16 (12.02 mg/mL; MeOH).Optical purity: >99.5% ee. Note: the optical purity assessment was madeon the methyl ester derivative of Cap-51, which was prepared under astandard TMSCHN₂ (benzene/MeOH) esterification protocol. HPLC analyticalconditions: column, CHIRALPAK® AD-H (4.6×250 mm, 5 μm); solvent, 95%heptane/5% IPA (isocratic); flow rate, 1 mL/min; temperature, 35° C.; UVmonitored at 205 nm.

[Note: Cap-51 could also be purchased from Flamm.]

Cap-52 (Same as Cap-12)

(S)-2-(Methoxycarbonylamino)propanoic acid

Cap-52 was synthesized from L-alanine according to the proceduredescribed for the synthesis of Cap-51. For characterization purposes, aportion of the crude material was purified by a reverse phase HPLC(H₂O/methanol/TFA) to afford Cap-52 as a colorless viscous oil. ¹H NMR(DMSO-d₆, δ=2.5 ppm, 500 MHz): 12.49 (br s, 1H), 7.43 (d, J=7.3, 0.88H),7.09 (app br s, 0.12H), 3.97 (m, 1H), 3.53 (s, 3H), 1.25 (d, J=7.3, 3H).

Cap-53 to Cap-64

Cap-53 to Cap-64 were prepared from appropriate starting materialsaccording to the procedure described for the synthesis of Cap-51, withnoted modifications if any.

Cap Structure Data Cap-53a: (R) Cap-53b: (S) ((S)- 2-(methoxy- carbonyl-amino)butanoic acid)

¹H NMR (DMSO-d₆, δ = 2.5 ppm, 500 MHz): δ 12.51 (br s, 1H), 7.4 (d, J =7.9, 0.9H), 7.06 (app s, 0.1H), 3.86-3.82 (m, 1H), 3.53 (s, 3H),1.75-1.67 (m, 1H), 1.62-1.54 (m, 1H), 0.88 (d, J = 7.3, 3H). RT = 0.77minutes (Cond. 2); LC- MS: Anal. Calcd. for [M + Na]⁺ C₆H₁₁NNaO₄:184.06; found 184.07. HRMS Calcd. for [M + Na]⁺ C₆H₁₁NNaO₄: 184.0586;found 184.0592. Cap-54a: (R) Cap-54b: (S) ((S)- 2-cyclopropyl-2-(methoxy-carbonyl- amino)acetic acid)

¹H NMR (DMSO-d₆, δ = 2.5 ppm, 500 MHz): δ 12.48 (s, 1H), 7.58 (d, J =7.6, 0.9H), 7.25 (app s, 0.1H), 3.52 (s, 3H), 3.36-3.33 (m, 1H),1.10-1.01 (m, 1H), 0.54-0.49 (m, 1H), 0.46-0.40 (m, 1H), 0.39-0.35 (m,1H), 0.31-0.21 (m, 1H). HRMS Calcd. for [M + H]⁺ C₇H₁₂NO₄: 174.0766;found 174.0771 Cap-55

¹H NMR (DMSO-d₆, δ = 2.5 ppm, 500 MHz): δ 12.62 (s, 1H), 7.42 (d, J =8.2, 0.9H), 7.07 (app s, 0.1H), 5.80-5.72 (m, 1H), 5.10 (d, J = 17.1,1H), 5.04 (d, J = 10.4, 1H), 4.01-3.96 (m, 1H), 3.53 (s, 3H), 2.47-2.42(m, 1H), 2.35-2.29 (m, 1H). Cap-56 (S)-3-methoxy-2- (methoxy-carbonyl-amino)propanoic acid

¹H NMR (DMSO-d₆, δ = 2.5 ppm, 500 MHz): δ 12.75 (s, 1H), 7.38 (d, J =8.3, 0.9H), 6.96 (app s, 0.1H), 4.20-4.16 (m, 1H), 3.60-3.55 (m, 2H),3.54 (s, 3H), 3.24 (s, 3H). Cap-57

¹H NMR (DMSO-d₆, δ = 2.5 ppm, 500 MHz): δ 12.50 (s, 1H), 8.02 (d, J =7.7, 0.08H), 7.40 (d, J = 7.9, 0.76H), 7.19 (d, J = 8.2, 0.07H), 7.07(d, J = 6.7, 0.09H), 4.21-4.12 (m, 0.08H), 4.06-3.97 (m, 0.07H),3.96-3.80 (m, 0.85H), 3.53 (s, 3H), 1.69-1.51 (m, 2H), 1.39-1.26 (m,2H), 0.85 (t, J = 7.4, 3H). LC (Cond. 2): RT = 1.39 LC-MS: Anal. Calcd.for [M + H]⁺ C₇H₁₄NO₄: 176.09; found 176.06. Cap-58

¹H NMR (DMSO-d₆, δ = 2.5 ppm, 500 MHz): δ 12.63 (br s, 1H), 7.35 (s,1H), 7.31 (d, J = 8.2, 1H), 6.92 (s, 1H), 4.33- 4.29 (m, 1H), 3.54 (s,3H), 2.54 (dd, J = 15.5, 5.4, 1H), 2.43 (dd, J = 15.6, 8.0, 1H). RT =0.16 min (Cond. 2); LC-MS: Anal. Calcd. for [M + H]⁺ C₆H₁₁N₂O₅: 191.07;found 191.14. Cap-59a: (R) Cap-59b: (S)

¹H NMR (DMSO-d₆, δ = 2.5 ppm, 400 MHz): δ 12.49 (br s, 1H), 7.40 (d, J =7.3, 0.89H), 7.04 (br s, 0.11H), 4.00- 3.95 (m, 3H), 1.24 (d, J = 7.3,3H), 1.15 (t, J = 7.2, 3H). HRMS: Anal. Calcd. for [M + H]⁺ C₆H₁₂NO₄:162.0766; found 162.0771. Cap-60

The crude material was purified with a reverse phase HPLC (H₂O/MeOH/TFA)to afford a colorless viscous oil that crystallized to a white solidupon exposure to high vacuum. ¹H NMR (DMSO-d₆, δ = 2.5 ppm, 400 MHz): δ12.38 (br s, 1H), 7.74 (s, 0.82H), 7.48 (s, 0.18H), 3.54/3.51 (two s,3H), 1.30 (m, 2H), 0.98 (m, 2H). HRMS: Anal. Calcd. for [M + H]⁺C₆H₁₀NO₄: 160.0610; found 160.0604. Cap-61

¹H NMR (DMSO-d₆, δ = 2.5 ppm, 400 MHz): δ 12.27 (br s, 1H), 7.40 (br s,1H), 3.50 (s, 3H), 1.32 (s, 6H). HRMS: Anal. Calcd. for [M + H]⁺C₆H₁₂NO₄: 162.0766; found 162.0765. Cap-62

¹H NMR (DMSO-d₆, δ = 2.5 ppm, 400 MHz): δ 12.74 (br s, 1H), 4.21 (d, J =10.3, 0.6H), 4.05 (d, J = 10.0, 0.4H), 3.62/3.60 (two singlets, 3H), 3.0(s, 3H), 2.14-2.05 (m, 1H), 0.95 (d, J = 6.3, 3H), 0.81 (d, J = 6.6,3H). LC-MS: Anal. Calcd. for [M − H]⁻ C₈H₁₄NO₄: 188.09; found 188.05.Cap-63

[Note: the reaction was allowed to run for longer than what was notedfor the general procedure.] ¹H NMR (DMSO- d₆, δ = 2.5 ppm, 400 MHz):12.21 (br s, 1H), 7.42 (br s, 1H), 3.50 (s, 3H), 2.02- 1.85 (m, 4H),1.66-1.58 (m, 4H). LC- MS: Anal. Calcd. for [M + H]⁺ C₈H₁₄NO₄: 188.09;found 188.19. Cap-64

[Note: the reaction was allowed to run for longer than what was notedfor the general procedure.] ¹H NMR (DMSO- d₆, δ = 2.5 ppm, 400 MHz):12.35 (br s, 1H), 7.77 (s, 0.82H), 7.56/7.52 (overlapping br s, 0.18H),3.50 (s, 3H), 2.47-2.40 (m, 2H), 2.14-2.07 (m, 2H), 1.93-1.82 (m, 2H).

Cap-65

Methyl chloroformate (0.65 mL, 8.39 mmol) was added dropwise over 5 minto a cooled (ice-water) mixture of Na₂CO₃ (0.449 g, 4.23 mmol), NaOH(8.2 mL of 1M/H₂O, 8.2 mmol) and (S)-2-amino-3-hydroxy-3-methylbutanoicacid (1.04 g, 7.81 mmol). The reaction mixture was stirred for 45 min,and then the cooling bath was removed and stirring was continued for anadditional 3.75 hr. The reaction mixture was washed with CH₂Cl₂, and theaqueous phase was cooled with ice-water bath and acidified withconcentrated HCl to a pH region of 1-2. The volatile component wasremoved in vacuo and the residue was taken up in a 2:1 mixture ofMeOH/CH₂Cl₂ (15 mL) and filtered, and the filterate was rotervaped toafford Cap-65 as a white semi-viscous foam (1.236 g). ¹H NMR (DMSO-d₆,δ=2.5 ppm, 400 MHz): δ 6.94 (d, J=8.5, 0.9; H), 6.53 (br s, 0.1H), 3.89(d, J=8.8, 1H), 2.94 (s, 3H), 1.15 (s, 3H), 1.13 (s, 3H).

Cap-66 and Cap-67 were prepared from appropriate commercially availablestarting materials by employing the procedure described for thesynthesis of Cap-65.

Cap-66

¹H NMR (DMSO-d₆, δ=2.5 ppm, 400 MHz): δ 12.58 (br s, 1H), 7.07 (d,J=8.3, 0.13H), 6.81 (d, J=8.8, 0.67H), 4.10-4.02 (m, 1.15H), 3.91 (dd,J=9.1, 3.5, 0.85H), 3.56 (s, 3H), 1.09 (d, J=6.2, 3H). [Note: only thedominant signals of NH were noted].

Cap-67

¹H NMR (DMSO-d₆, δ=2.5 ppm, 400 MHz): 12.51 (br s, 1H), 7.25 (d, J=8.4,0.75H), 7.12 (br d, J=0.4, 0.05H), 6.86 (br s, 0.08H), 3.95-3.85 (m,2H), 3.54 (s, 3H), 1.08 (d, J=6.3, 3H). [Note: only the dominant signalsof NH were noted].

Cap-68

Methyl chloroformate (0.38 ml, 4.9 mmol) was added drop-wise to amixture of 1N NaOH (aq) (9.0 ml, 9.0 mmol), 1M NaHCO₃ (aq) (9.0 ml, 9.0mol), L-aspartic acid β-benzyl ester (1.0 g, 4.5 mmol) and dioxane (9ml). The reaction mixture was stirred at ambient conditions for 3 hr,and then washed with ethyl acetate (50 ml, 3×). The aqueous layer wasacidified with 12N HCl to a pH ˜1-2, and extracted with ethyl acetate(3×50 ml). The combined organic layers were washed with brine, dried(Na₂SO₄), filtered, and concentrated in vacuo to afford Cap-68 as alight yellow oil (1.37 g; mass is above theoretical yield, and theproduct was used without further purification). ¹H NMR (DMSO-d₆, δ=2.5ppm, 500 MHz): δ 12.88 (br s, 1H), 7.55 (d, J=8.5, 1H), 7.40-7.32 (m,5H), 5.13 (d, J=12.8, 1H), 5.10 (d, J=12.9, 1H), 4.42-4.38 (m, 1H), 3.55(s, 3H), 2.87 (dd, J=16.2, 5.5, 1H), 2.71 (dd, J=16.2, 8.3, 1H). LC(Cond. 2): RT=1.90 min; LC-MS: Anal. Calcd. for [M+H]⁺ C₁₃H₁₆NO₆:282.10; found 282.12.

Cap-69a and Cap-69b

NaCNBH₃ (2.416 g, 36.5 mmol) was added in batches to a chilled (˜15° C.)water (17 mL)/MeOH (10 mL) solution of alanine (1.338 g, 15.0 mmol). Afew minutes later acetaldehyde (4.0 mL, 71.3 mmol) was added drop-wiseover 4 min, the cooling bath was removed, and the reaction mixture wasstirred at ambient condition for 6 hr. An additional acetaldehyde (4.0mL) was added and the reaction was stirred for 2 hr. Concentrated HClwas added slowly to the reaction mixture until the pH reached ˜1.5, andthe resulting mixture was heated for 1 hr at 40° C. Most of the volatilecomponent was removed in vacuo and the residue was purified with aDOWEX® 50WX8-100 ion-exchange resin (column was washed with water, andthe compound was eluted with dilute NH₄OH, prepared by mixing 18 ml ofNH₄OH and 282 ml of water) to afford Cap-69 (2.0 g) as an off-white softhygroscopic solid. ¹H NMR (DMSO-d₆, δ=2.5 ppm, 400 MHz): δ 3.44 (q,J=7.1, 1H), 2.99-2.90 (m, 2H), 2.89-2.80 (m, 2H), 1.23 (d, J=7.1, 3H),1.13 (t, J=7.3, 6H).

Cap-70 to Cap-74x

Cap-70 to Cap-74x were prepared according to the procedure described forthe synthesis of Cap-69 by employing appropriate starting materials.

Cap-70a: (R) Cap-70b: (S)

¹H NMR (DMSO-d₆, δ = 2.5 ppm, 400 MHz): δ 3.42 (q, J = 7.1, 1H),2.68-2.60 (m, 4H), 1.53- 1.44 (m, 4H), 1.19 (d, J = 7.3, 3H), 0.85 (t, J= 7.5, 6H). LC-MS: Anal. Calcd. for [M + H]⁺ C₉H2₀NO₂: 174.15; found174.13. Cap-71a: (R) Cap-71b: (S)

¹H NMR (DMSO-d₆, δ = 2.5 ppm, 500 MHz): δ 3.18-3.14 (m, 1H), 2.84-2.77(m, 2H), 2.76-2.68 (m, 2H), 1.69-1.54 (m, 2H), 1.05 (t, J = 7.2, 6H),0.91 (t, J= 7.3, 3H). LC-MS: Anal. Calcd. for [M + H]⁺ C₈H₁₈NO₂: 160.13;found 160.06. Cap-72

¹H NMR (DMSO-d₆, δ = 2.5 ppm, 400 MHz): δ 2.77-2.66 (m, 3H), 2.39-2.31(m, 2H), 1.94-1.85 (m, 1H), 0.98 (t, J = 7.1, 6H), 0.91 (d, J = 6.5,3H), 0.85 (d, J = 6.5, 3H). LC-MS: Anal. Calcd. for [M + H]⁺ C₉H₂₀NO₂:174.15; found 174.15. Cap-73

¹H NMR (DMSO-d₆, δ = 2.5 ppm, 500 MHz): δ 9.5 (br s, 1H), 3.77 (dd, J =10.8, 4.1, 1H), 3.69- 3.61 (m, 2H), 3.26 (s, 3H), 2.99-2.88 (m, 4H),1.13 (t, J = 7.2, 6H). Cap-74

¹H NMR (DMSO-d₆, δ = 2.5 ppm, 500 MHz): δ 7.54 (s, 1H), 6.89 (s, 1H),3.81 (t, J = 6.6, k, 1H), 2.82-2.71 (m, 4H), 2.63 (dd, J = 15.6, 7.0,1H), 2.36 (dd, J = 15.4, 6.3, 1H), 1.09 (t, J = 7.2, 6H). RT = 0.125minutes (Cond. 2); LC-MS: Anal. Calcd. for [M + H]⁺ C₈H₁₇N₂O₃: 189.12;found 189.13. Cap-74x

LC-MS: Anal. Calcd. for [M + H]⁺ C₁₀H₂₂NO₂: 188.17; found 188.21

Cap-75

Cap-75, Step a

NaBH₃CN (1.6 g, 25.5 mmol) was added to a cooled (ice/water bath) water(25 ml)/methanol (15 ml) solution of H-D-Ser-OBzl HCl (2.0 g, 8.6 mmol).Acetaldehyde (1.5 ml, 12.5 mmol) was added drop-wise over 5 min, thecooling bath was removed, and the reaction mixture was stirred atambient condition for 2 hr. The reaction was carefully quenched with 12NHCl and concentrated in vacuo. The residue was dissolved in water andpurified with a reverse phase HPLC (MeOH/H₂O/TFA) to afford the TFA saltof (R)-benzyl 2-(diethylamino)-3-hydroxypropanoate as a colorlessviscous oil (1.9 g). ¹H NMR (DMSO-d₆, δ=2.5 ppm, 500 MHz): δ 9.73 (br s,1H), 7.52-7.36 (m, 5H), 5.32 (d, J=12.2, 1H), 5.27 (d, J=12.5, 1H),4.54-4.32 (m, 1H), 4.05-3.97 (m, 2H), 3.43-3.21 (m, 4H), 1.23 (t, J=7.2,6H). LC-MS (Cond. 2): RT=1.38 min; LC-MS: Anal. Calcd. for [M+H]⁺C₁₄H₂₂NO₃: 252.16; found 252.19.

Cap-75

NaH (0.0727 g, 1.82 mmol, 60%) was added to a cooled (ice-water) THF(3.0 mL) solution of the TFA salt (R)-benzyl2-(diethylamino)-3-hydroxypropanoate (0.3019 g, 0.8264 mmol) preparedabove, and the mixture was stirred for 15 min. Methyl iodide (56 μL,0.90 mmol) was added and stirring was continued for 18 hr while allowingthe bath to thaw to ambient condition. The reaction was quenched withwater and loaded onto a MeOH pre-conditioned MCX (6 g) cartridge, andwashed with methanol followed by compound elution with 2N NH₃/Methanol.Removal of the volatile component in vacuo afforded Cap-75, contaminatedwith (R)-2-(diethylamino)-3-hydroxypropanoic acid, as a yellowsemi-solid (100 mg). The product was used as is without furtherpurification.

Cap-76

NaCNBH₃ (1.60 g, 24.2 mmol) was added in batches to a chilled (˜15° C.)water/MeOH (12 mL each) solution of(S)-4-amino-2-(tert-butoxycarbonylamino) butanoic acid (2.17 g, 9.94mmol). A few minutes later acetaldehyde (2.7 mL, 48.1 mmol) was addeddrop-wise over 2 min, the cooling bath was removed, and the reactionmixture was stirred at ambient condition for 3.5 hr. An additionalacetaldehyde (2.7 mL, 48.1 mmol) was added and the reaction was stirredfor 20.5 hr. Most of the MeOH component was removed in vacuo, and theremaining mixture was treated with concentrated HCl until its pH reached˜1.0 and then heated for 2 hr at 40° C. The volatile component wasremoved in vacuo, and the residue was treated with 4 M HCl/dioxane (20mL) and stirred at ambient condition for 7.5 hr. The volatile componentwas removed in vacuo and the residue was purified with DOWEX® 50WX8-100ion-exchange resin (column was washed with water and the compound waseluted with dilute NH₄OH, prepared from 18 ml of NH₄OH and 282 ml ofwater) to afford intermediate (S)-2-amino-4-(diethylamino)butanoic acidas an off-white solid (1.73 g).

Methyl chloroformate (0.36 mL, 4.65 mmol) was added drop-wise over 11min to a cooled (ice-water) mixture of Na₂CO₃ (0.243 g, 2.29 mmol), NaOH(4.6 mL of 1M/H₂O, 4.6 mmol) and the above product (802.4 mg). Thereaction mixture was stirred for 55 min, and then the cooling bath wasremoved and stirring was continued for an additional 5.25 hr. Thereaction mixture was diluted with equal volume of water and washed withCH₂Cl₂ (30 mL, 2×), and the aqueous phase was cooled with ice-water bathand acidified with concentrated HCl to a pH region of 2. The volatilecomponent was then removed in vacuo and the crude material wasfree-based with MCX resin (6.0 g; column was washed with water, andsample was eluted with 2.0 M NH₃/MeOH) to afford impure Cap-76 as anoff-white solid (704 mg). ¹H NMR (MeOH-d₄, δ=3.29 ppm, 400 MHz): δ 3.99(dd, J=7.5, 4.7, 1H), 3.62 (s, 3H), 3.25-3.06 (m, 6H), 2.18-2.09 (m,1H), 2.04-1.96 (m, 1H), 1.28 (t, J=7.3, 6H). LC-MS: Anal. Calcd. for[M+H]⁺ C₁₀H₂₁N₂O₄: 233.15; found 233.24.

Cap-77a and Cap-77b

The synthesis of Cap-77 was conducted according to the proceduredescribed for Cap-7 by using 7-azabicyclo[2.2.1]heptane for the SN₂displacement step, and by effecting the stereoisomeric separation of theintermediate benzyl 2-(7-azabicyclo[2.2.1]heptan-7-yl)-2-phenylacetateusing the following condition: the intermediate (303.7 mg) was dissolvedin ethanol, and the resulting solution was injected on a chiral HPLCcolumn (Chiracel AD-H column, 30×250 mm, 5 um) eluting with 90% CO₂-10%EtOH at 70 mL/min, and a temperature of 35° C. to provide 124.5 mg ofstereoisomer-1 and 133.8 mg of stereoisomer-2. These benzyl esters werehydrogenolysed according to the preparation of Cap-7 to provide Cap-77:¹H NMR (DMSO-d₆, δ=2.5 ppm, 400 MHz): δ 7.55 (m, 2H), 7.38-7.30 (m, 3H),4.16 (s, 1H), 3.54 (app br s, 2H), 2.08-1.88 (m, 4 H), 1.57-1.46 (m,4H). LC (Cond. 1): RT=0.67 min; LC-MS: Anal. Calcd. for [M+H]⁺C₁₄H₁₈NO₂: 232.13; found 232.18. HRMS: Anal. Calcd. for [M+H]⁺C₁₄H₁₈NO₂: 232.1338; found 232.1340.

Cap-78

NaCNBH₃ (0.5828 g, 9.27 mmol) was added to a mixture of the HCl salt of(R)-2-(ethylamino)-2-phenylacetic acid (an intermediate in the synthesisof Cap-3; 0.9923 mg, 4.60 mmol) and(1-ethoxycyclopropoxy)trimethylsilane (1.640 g, 9.40 mmol) in MeOH (10mL), and the semi-heterogeneous mixture was heated at 50° C. with an oilbath for 20 hr. More (1-ethoxycyclopropoxy)trimethylsilane (150 mg, 0.86mmol) and NaCNBH₃ (52 mg, 0.827 mmol) were added and the reactionmixture was heated for an additional 3.5 hr. It was then allowed to coolto ambient temperature and acidified to a ˜pH region of 2 withconcentrated HCl, and the mixture was filtered and the filtrate wasrotervaped. The resulting crude material was taken up in i-PrOH (6 mL)and heated to effect dissolution, and the non-dissolved part wasfiltered off and the filtrate concentrated in vacuo. About ⅓ of theresultant crude material was purified with a reverse phase HPLC(H₂O/MeOH/TFA) to afford the TFA salt of Cap-78 as a colorless viscousoil (353 mg). ¹H NMR (DMSO-d₆, δ=2.5 ppm, 400 MHz; after D₂O exchange):δ 7.56-7.49 (m, 5H), 5.35 (S, 1H), 3.35 (m, 1H), 3.06 (app br s, 1H),2.66 (m, 1H), 1.26 (t, J=7.3, 3H), 0.92 (m, 1H), 0.83-0.44 (m, 3H). LC(Cond. 1): RT=0.64 min; LC-MS: Anal. Calcd. for [M+H]⁺ C₁₃H₁₈NO₂:220.13; found 220.21. HRMS: Anal. Calcd. for [M+H]⁺ C₁₃H₁₈NO₂: 220.1338;found 220.1343.

Cap-79

Ozone was bubbled through a cooled (−78° C.) CH₂Cl₂ (5.0 mL) solutionCap-55 (369 mg, 2.13 mmol) for about 50 min until the reaction mixtureattained a tint of blue color. Me₂S (10 pipette drops) was added, andthe reaction mixture was stirred for 35 min. The −78° C. bath wasreplaced with a −10° C. bath and stirring continued for an additional 30min, and then the volatile component was removed in vacuo to afford acolorless viscous oil.

NaBH₃CN (149 mg, 2.25 mmol) was added to a MeOH (5.0 mL) solution of theabove crude material and morpholine (500 μL, 5.72 mmol) and the mixturewas stirred at ambient condition for 4 hr. It was cooled to ice-watertemperature and treated with concentrated HCl to bring its pH to ˜2.0,and then stirred for 2.5 hr. The volatile component was removed invacuo, and the residue was purified with a combination of MCX resin(MeOH wash; 2.0 N NH₃/MeOH elution) and a reverse phase HPLC(H₂O/MeOH/TFA) to afford Cap-79 containing unknown amount of morpholine.

In order to consume the morpholine contaminant, the above material wasdissolved in CH₂Cl₂ (1.5 mL) and treated with Et₃N (0.27 mL, 1.94 mmol)followed by acetic anhydride (0.10 mL, 1.06 mmol) and stirred at ambientcondition for 18 hr. THF (1.0 mL) and H₂O (0.5 mL) were added andstirring continued for 1.5 hr. The volatile component was removed invacuo, and the resultant residue was passed through MCX resin (MeOHwash; 2.0 N NH₃/MeOH elution) to afford impure Cap-79 as a brown viscousoil, which was used for the next step without further purification.

Cap-80a and Cap-80b

SOCl₂ (6.60 mL, 90.5 mmol) was added drop-wise over 15 min to a cooled(ice-water) mixture of (S)-3-amino-4-(benzyloxy)-4-oxobutanoic acid(10.04 g, 44.98 mmol) and MeOH (300 mL), the cooling bath was removedand the reaction mixture was stirred at ambient condition for 29 hr.Most of the volatile component was removed in vacuo and the residue wascarefully partitioned between EtOAc (150 mL) and saturated NaHCO₃solution. The aqueous phase was extracted with EtOAc (150 mL, 2×), andthe combined organic phase was dried (MgSO₄), filtered, and concentratedin vacuo to afford (S)-1-benzyl 4-methyl 2-aminosuccinate as a colorlessoil (9.706 g). ¹H NMR (DMSO-d₆, δ=2.5 ppm, 400 MHz): δ 7.40-7.32 (m,5H), 5.11 (s, 2H), 3.72 (app t, J=6.6, 1H), 3.55 (s, 3H), 2.68 (dd,J=15.9, 6.3, 1H), 2.58 (dd, J=15.9, 6.8, 1H), 1.96 (s, 2H). LC (Cond.1): RT=0.90 min; LC-MS: Anal. Calcd. for [M+H]⁺ C₁₂H₁₆NO₄: 238.11; found238.22.

Pb(NO₃)₂ (6.06 g, 18.3 mmol) was added over 1 min to a CH₂Cl₂ (80 mL)solution of (S)-1-benzyl 4-methyl 2-aminosuccinate (4.50 g, 19.0 mmol),9-bromo-9-phenyl-9H-fluorene (6.44 g, 20.0 mmol) and Et₃N (3.0 mL, 21.5mmol), and the heterogeneous mixture was stirred at ambient conditionfor 48 hr. The mixture was filtered and the filtrate was treated withMgSO₄ and filtered again, and the final filtrate was concentrated. Theresulting crude material was submitted to a BIOTAGE® purification (350 gsilica gel, CH₂Cl₂ elution) to afford (S)-1-benzyl 4-methyl2-(9-phenyl-9H-fluoren-9-ylamino)succinate as highly viscous colorlessoil (7.93 g). ¹H NMR (DMSO-d₆, δ=2.5 ppm, 400 MHz): δ 7.82 (m, 2H),7.39-7.13 (m, 16H), 4.71 (d, J=12.4, 1H), 4.51 (d, J=12.6, 1H), 3.78 (d,J=9.1, NH), 3.50 (s, 3H), 2.99 (m, 1H), 2.50-2.41 (m, 2H, partiallyoverlapped with solvent). LC (Cond. 1): RT=2.16 min; LC-MS: Anal. Calcd.for [M+H]⁺ C₃₁H₂₈NO₄: 478.20; found 478.19.

LiHMDS (9.2 mL of 1.0 M/THF, 9.2 mmol) was added drop-wise over 10 minto a cooled (−78° C.) THF (50 mL) solution of (S)-1-benzyl 4-methyl2-(9-phenyl-9H-fluoren-9-ylamino)succinate (3.907 g, 8.18 mmol) andstirred for ˜1 hr. MeI (0.57 mL, 9.2 mmol) was added drop-wise over 8min to the mixture, and stirring was continued for 16.5 hr whileallowing the cooling bath to thaw to room temperature. After quenchingwith saturated NH₄Cl solution (5 mL), most of the organic component wasremoved in vacuo and the residue was partitioned between CH₂Cl₂ (100 mL)and water (40 mL). The organic layer was dried (MgSO₄), filtered, andconcentrated in vacuo, and the resulting crude material was purifiedwith a BIOTAGE® (350 g silica gel; 25% EtOAc/hexanes) to afford 3.65 gof a 2S/3S and 2S/3R diastereomeric mixtures of 1-benzyl 4-methyl3-methyl-2-(9-phenyl-9H-fluoren-9-ylamino)succinate in ˜1.0:0.65 ratio(¹H NMR). The stereochemistry of the dominant isomer was not determinedat this juncture, and the mixture was submitted to the next step withoutseparation. Partial ¹H NMR data (DMSO-d₆, δ=2.5 ppm, 400 MHz): majordiastereomer, δ 4.39 (d, J=12.3, 1H of CH₂), 3.33 (s, 3H, overlappedwith H₂O signal), 3.50 (d, J=10.9, NH), 1.13 (d, J=7.1, 3H); minordiastereomer, δ 4.27 (d, J=12.3, 1H of CH₂), 3.76 (d, J=10.9, NH), 3.64(s, 3H), 0.77 (d, J=7.0, 3H). LC (Cond. 1): RT=2.19 min; LC-MS: Anal.Calcd. for [M+H]⁺ C₃₂H₃₀NO₄: 492.22; found 492.15.

Diisobutylaluminum hydride (20.57 ml of 1.0 M in hexanes, 20.57 mmol)was added drop-wise over 10 min to a cooled (−78° C.) THF (120 mL)solution of (2S)-1-benzyl 4-methyl3-methyl-2-(9-phenyl-9H-fluoren-9-ylamino)succinate (3.37 g, 6.86 mmol)prepared above, and stirred at −78° C. for 20 hr. The reaction mixturewas removed from the cooling bath and rapidly poured into ˜1M H₃PO₄/H₂O(250 mL) with stirring, and the mixture was extracted with ether (100mL, 2×). The combined organic phase was washed with brine, dried(MgSO₄), filtered and concentrated in vacuo. A silica gel mesh of thecrude material was prepared and submitted to chromatography (25%EtOAc/hexanes; gravity elution) to afford 1.1 g of (2S,3S)-benzyl4-hydroxy-3-methyl-2-(9-phenyl-9H-fluoren-9-ylamino)butanoate,contaminated with benzyl alcohol, as a colorless viscous oil and(2S,3R)-benzyl4-hydroxy-3-methyl-2-(9-phenyl-9H-fluoren-9-ylamino)butanoate containingthe (2S,3R) stereoisomer as an impurity. The later sample wasresubmitted to the same column chromatography purification conditions toafford 750 mg of purified material as a white foam. [Note: the (2S,3S)isomer elutes before the (2S,3R) isomer under the above condition].(2S,3S) isomer: ¹H NMR (DMSO-d₆, δ=2.5 ppm, 400 MHz): 7.81 (m, 2H),7.39-7.08 (m, 16H), 4.67 (d, J=12.3, 1H), 4.43 (d, J=12.4, 1H), 4.21(app t, J=5.2, OH), 3.22 (d, J=10.1, NH), 3.17 (m, 1H), 3.08 (m, 1H),˜2.5 (m, 1H, overlapped with the solvent signal), 1.58 (m, 1H), 0.88 (d,J=6.8, 3H). LC (Cond. 1): RT=2.00 min; LC-MS: Anal. Calcd. for [M+H]⁺C₃₁H₃₀NO₃: 464.45; found 464.22. (2S,3R) isomer: ¹H NMR (DMSO-d₆, δ=2.5ppm, 400 MHz): 7.81 (d, J=7.5, 2H), 7.39-7.10 (m, 16H), 4.63 (d, J=12.1,1H), 4.50 (app t, J=4.9, 1H), 4.32 (d, J=12.1, 1H), 3.59-3.53 (m, 2H),3.23 (m, 1H), 2.44 (dd, J=9.0, 8.3, 1H), 1.70 (m, 1H), 0.57 (d, J=6.8,3H). LC (Cond. 1): RT=1.92 min; LC-MS: Anal. Calcd. for [M+H]⁺C₃₁H₃₀NO₃: 464.45; found 464.52.

The relative stereochemical assignments of the DIBAL-reduction productswere made based on NOE studies conducted on lactone derivatives preparedfrom each isomer by employing the following protocol: LiHMDS (50 μL of1.0 M/THF, 0.05 mmol) was added to a cooled (ice-water) THF (2.0 mL)solution of (2S,3S)-benzyl4-hydroxy-3-methyl-2-(9-phenyl-9H-fluoren-9-ylamino)butanoate (62.7 mg,0.135 mmol), and the reaction mixture was stirred at similar temperaturefor ˜2 hr. The volatile component was removed in vacuo and the residuewas partitioned between CH₂Cl₂ (30 mL), water (20 mL) and saturatedaqueous NH₄Cl solution (1 mL). The organic layer was dried (MgSO₄),filtered, and concentrated in vacuo, and the resulting crude materialwas submitted to a BIOTAGE® purification (40 g silica gel; 10-15%EtOAc/hexanes) to afford(3S,4S)-4-methyl-3-(9-phenyl-9H-fluoren-9-ylamino)dihydrofuran-2(3H)-oneas a colorless film of solid (28.1 mg). (2S,3R)-benzyl4-hydroxy-3-methyl-2-(9-phenyl-9H-fluoren-9-ylamino)butanoate waselaborated similarly to(3S,4R)-4-methyl-3-(9-phenyl-9H-fluoren-9-ylamino)dihydrofuran-2(3H)-one.(3S,4S)-lactone isomer: ¹H NMR (DMSO-d₆, δ=2.5 ppm, 400 MHz), 7.83 (d,J=7.5, 2H), 7.46-7.17 (m, 11H), 4.14 (app t, J=8.3, 1H), 3.60 (d, J=5.8,NH), 3.45 (app t, J=9.2, 1H), ˜2.47 (m, 1H, partially overlapped withsolvent signal), 2.16 (m, 1H), 0.27 (d, J=6.6, 3H). LC (Cond. 1):RT=1.98 min; LC-MS: Anal. Calcd. for [M+Na]⁺ C₂₄H₂₁NNaO₂: 378.15; found378.42. (3S,4R)-lactone isomer: ¹H NMR (DMSO-d₆, δ=2.5 ppm, 400 MHz),7.89 (d, J=7.6, 1H), 7.85 (d, J=7.3, 1H), 7.46-7.20 (m, 11H), 3.95 (dd,J=9.1, 4.8, 1H), 3.76 (d, J=8.8, 1H), 2.96 (d, J=3.0, NH), 2.92 (dd,J=6.8, 3, NCH), 1.55 (m, 1H), 0.97 (d, J=7.0, 3H). LC (Cond. 1): RT=2.03min; LC-MS: Anal. Calcd. for [M+Na]⁺ C₂₄H₂₁NNaO₂: 378.15; found 378.49.

TBDMS-Cl (48 mg, 0.312 mmol) followed by imidazole (28.8 mg, 0.423 mmol)were added to a CH₂Cl₂ (3 ml) solution of (2S,3S)-benzyl4-hydroxy-3-methyl-2-(9-phenyl-9H-fluoren-9-ylamino)butanoate (119.5 mg,0.258 mmol), and the mixture was stirred at ambient condition for 14.25hr. The reaction mixture was then diluted with CH₂Cl₂ (30 mL) and washedwith water (15 mL), and the organic layer was dried (MgSO₄), filtered,and concentrated in vacuo. The resultant crude material was purifiedwith a BIOTAGE® (40 g silica gel; 5% EtOAc/hexanes) to afford(2S,3S)-benzyl4-(tert-butyldimethylsilyloxy)-3-methyl-2-(9-phenyl-9H-fluoren-9-ylamino)butanoate,contaminated with TBDMS based impurities, as a colorless viscous oil(124.4 mg). (2S,3R)-benzyl4-hydroxy-3-methyl-2-(9-phenyl-9H-fluoren-9-ylamino)butanoate waselaborated similarly to (2S,3R)-benzyl4-(tert-butyldimethylsilyloxy)-3-methyl-2-(9-phenyl-9H-fluoren-9-ylamino)butanoate.(2S,3S)-silyl ether isomer: ¹H NMR (DMSO-d₆, δ=2.5 ppm, 400 MHz), 7.82(d, J=4.1, 1H), 7.80 (d, J=4.0, 1H), 7.38-7.07 (m, 16 H), 4.70 (d,J=12.4, 1H), 4.42 (d, J=12.3, 1H), 3.28-3.19 (m, 3H), 2.56 (dd, J=10.1,5.5, 1H), 1.61 (m, 1H), 0.90 (d, J=6.8, 3H), 0.70 (s, 9H), −0.13 (s,3H), −0.16 (s, 3H). LC (Cond. 1, where the run time was extended to 4min): RT=3.26 min; LC-MS: Anal. Calcd. for [M+H]⁺ C₃₇H₄₄NO₃Si: 578.31;found 578.40. (2S,3R)-silyl ether isomer: ¹H NMR (DMSO-d₆, δ=2.5 ppm,400 MHz), 7.82 (d, J=3.0, 1H), 7.80 (d, J=3.1, 1H), 7.39-7.10 (m, 16H),4.66 (d, J=12.4, 1H), 4.39 (d, J=12.4, 1H), 3.61 (dd, J=9.9, 5.6, 1H),3.45 (d, J=9.5, 1H), 3.41 (dd, J=10, 6.2, 1H), 2.55 (dd, J=9.5, 7.3,1H), 1.74 (m, 1H), 0.77 (s, 9H), 0.61 (d, J=7.1, 3H), −0.06 (s, 3H),−0.08 (s, 3H).

A balloon of hydrogen was attached to a mixture of (2S,3S)-benzyl4-(tert-butyldimethylsilyloxy)-3-methyl-2-(9-phenyl-9H-fluoren-9-ylamino)butanoate(836 mg, 1.447 mmol) and 10% Pd/C (213 mg) in EtOAc (16 mL) and themixture was stirred at room temperature for ˜21 hr, where the balloonwas recharged with H₂ as necessary. The reaction mixture was dilutedwith CH₂Cl₂ and filtered through a pad of diatomaceous earth(CELITE®-545), and the pad was washed with EtOAc (200 mL), EtOAc/MeOH(1:1 mixture, 200 mL) and MeOH (750 mL). The combined organic phase wasconcentrated, and a silica gel mesh was prepared from the resultingcrude material and submitted to a flash chromatography (8:2:1 mixture ofEtOAc/i-PrOH/H₂O) to afford(2S,3S)-2-amino-4-(tert-butyldimethylsilyloxy)-3-methylbutanoic acid asa white fluffy solid (325 mg). (2S,3R)-benzyl4-(tert-butyldimethylsilyloxy)-3-methyl-2-(9-phenyl-9H-fluoren-9-ylamino)butanoatewas similarly elaborated to(2S,3R)-2-amino-4-(tert-butyldimethylsilyloxy)-3-methylbutanoic acid.(2S,3S)-amino acid isomer: ¹H NMR (methanol-d₄, δ=3.29 ppm, 400 MHz),3.76 (dd, J=10.5, 5.2, 1H), 3.73 (d, J=3.0, 1H), 3.67 (dd, J=10.5, 7.0,1H), 2.37 (m, 1H), 0.97 (d, J=7.0, 3H), 0.92 (s, 9H), 0.10 (s, 6H).LC-MS: Anal. Calcd. for [M+H]⁺ C₁₁H₂₆NO₃Si: 248.17; found 248.44.(2S,3R)-amino acid isomer: ¹H NMR (methanol-d₄, δ=3.29 ppm, 400 MHz),3.76-3.75 (m, 2H), 3.60 (d, J=4.1, 1H), 2.16 (m, 1H), 1.06 (d, J=7.3,3H), 0.91 (s, 9H), 0.09 (s, 6H). Anal. Calcd. for [M+H]⁺ C₁₁H₂₆NO₃Si:248.17; found 248.44.

Water (1 mL) and NaOH (0.18 mL of 1.0 M/H₂O, 0.18 mmol) were added to amixture of(2S,3S)-2-amino-4-(tert-butyldimethylsilyloxy)-3-methylbutanoic acid(41.9 mg, 0.169 mmol) and Na₂CO₃ (11.9 mg, 0.112 mmol), and sonicatedfor about 1 min to effect dissolution of reactants. The mixture was thencooled with an ice-water bath, methyl chloroformate (0.02 mL, 0.259mmol) was added over 30 s, and vigorous stirring was continued atsimilar temperature for 40 min and then at ambient temperature for 2.7hr. The reaction mixture was diluted with water (5 mL), cooled withice-water bath and treated drop-wise with 1.0 N HCl aqueous solution(˜0.23 mL). The mixture was further diluted with water (10 mL) andextracted with CH₂Cl₂ (15 mL, 2×). The combined organic phase was dried(MgSO₄), filtered, and concentrated in vacuo to afford Cap-80a as anoff-white solid.(2S,3R)-2-amino-4-(tert-butyldimethylsilyloxy)-3-methylbutanoic acid wassimilarly elaborated to Cap-80b. Cap-80a: ¹H NMR (DMSO-d₆, δ=2.5 ppm,400 MHz), 12.57 (br s, 1H), 7.64 (d, J=8.3, 0.3H), 7.19 (d, J=8.8,0.7H), 4.44 (dd, J=8.1, 4.6, 0.3H), 4.23 (dd, J=8.7, 4.4, 0.7H),3.56/3.53 (two singlets, 3H), 3.48-3.40 (m, 2H), 2.22-2.10 (m, 1H), 0.85(s, 9H), ˜0.84 (d, 0.9H, overlapped with t-Bu signal), 0.79 (d, J=7,2.1H), 0.02/0.01/0.00 (three overlapping singlets, 6H). LC-MS: Anal.Calcd. for [M+Na]^(+C) ₁₃H₂₇NNaO₅Si: 328.16; found 328.46. Cap-80b: ¹HNMR (CDCl₃, δ=7.24 ppm, 400 MHz), 6.00 (br d, J=6.8, 1H), 4.36 (dd,J=7.1, 3.1, 1H), 3.87 (dd, J=10.5, 3.0, 1H), 3.67 (s, 3H), 3.58 (dd,J=10.6, 4.8, 1H), 2.35 (m, 1H), 1.03 (d, J=7.1, 3H), 0.90 (s, 9H), 0.08(s, 6H). LC-MS: Anal. Calcd. for [M+Na]⁺ C₁₃H₂₇NNaO₅Si: 328.16; found328.53. The crude products were utilized without further purification.

Cap-81

Prepared according to the protocol described by Falb et al., SyntheticCommunications, 23:2839 (1993).

Cap-82 to Cap-85

Cap-82 to Cap-85 were synthesized from appropriate starting materialsaccording to the procedure described for Cap-51 or Cap-13. The samplesexhibited similar spectral profiles as that of their stereoisomers(i.e., Cap-4, Cap-13, Cap-51 and Cap-52, respectively).

Cap-86

(2S,3R)-3-Methoxy-2-(methoxycarbonylamino)butanoic acid

To a mixture of O-methyl-L-threonine (3.0 g, 22.55 mmol), NaOH (0.902 g,22.55 mmol) in H₂O (15 mL) was added ClCO₂Me (1.74 mL, 22.55 mmol)dropwise at 0° C. The mixture was allowed to stir for 12 h and acidifiedto pH 1 using 1N HCl. The aqueous phase was extracted with EtOAc and(2×250 mL) and 10% MeOH in CH₂Cl₂ (250 mL) and the combined organicphases were concentrated under in vacuo to afford a colorless oil (4.18g, 97%) which was of sufficient purity for use in subsequent steps. ¹HNMR (400 MHz, CDCl₃) δ 4.19 (s, 1H), 3.92-3.97 (m, 1H), 3.66 (s, 3H),1.17 (d, J=7.7 Hz, 3H). LC-MS: Anal. Calcd. for C₇H₁₃NO₅: 191; found:190 (M−H)⁻.

Cap-87

To a mixture of L-homoserine (2.0 g, 9.79 mmol), Na₂CO₃ (2.08 g, 19.59mmol) in H₂O (15 mL) was added ClCO₂Me (0.76 mL, 9.79 mmol) dropwise at0° C. The mixture was allowed to stir for 48 h and acidified to pH 1using 1N HCl. The aqueous phase was extracted with EtOAc and (2×250 mL)and the combined organic phases were concentrated in vacuo to afford acolorless solid (0.719 g, 28%) which was of sufficient purity for use insubsequent steps. ¹H NMR (400 MHz, CDCl₃) δ 4.23 (dd, J=4.5, 9.1 Hz,1H), 3.66 (s, 3H), 3.43-3.49 (m, 2H), 2.08-2.14 (m, 1H), 1.82-1.89 (m,1H). LC-MS: Anal. Calcd. for C₇H₁₃NO₅: 191; found: 192 (M+H)⁺.

Cap-88

A mixture of L-valine (1.0 g, 8.54 mmol), 3-bromopyridine (1.8 mL, 18.7mmol), K₂CO₃ (2.45 g, 17.7 mmol) and CuI (169 mg, 0.887 mmol) in DMSO(10 mL) was heated at 100° C. for 12 h. The reaction mixture was cooledto rt, poured into H₂O (ca. 150 mL) and washed with EtOAc (×2). Theorganic layers were extracted with a small amount of H₂O and thecombined aq phases were acidified to ca. pH 2 with 6N HCl. The volumewas reduced to about one-third and 20 g of cation exchange resin(Strata) was added. The slurry was allowed to stand for 20 min andloaded onto a pad of cation exchange resin (Strata) (ca. 25 g). The padwas washed with H₂O (200 mL), MeOH (200 mL), and then NH₃ (3M in MeOH,2×200 mL). The appropriate fractions was concentrated in vacuo and theresidue (ca. 1.1 g) was dissolved in H₂O, frozen and lyophyllized. Thetitle compound was obtained as a foam (1.02 g, 62%). ¹H NMR (400 MHz,DMSO-d₆) δ 8.00 (s, br, 1H), 7.68-7.71 (m, 1H), 7.01 (s, br, 1H), 6.88(d, J=7.5 Hz, 1H), 5.75 (s, br, 1H), 3.54 (s, 1H), 2.04-2.06 (m, 1H),0.95 (d, J=6.0 Hz, 3H), 0.91 (d, J=6.6 Hz, 3H). LC-MS: Anal. Calcd. forC₁₀H₁₄N₂O₂: 194; found: 195 (M+H)⁺.

Cap-89

A mixture of L-valine (1.0 g, 8.54 mmol), 5-bromopyrimidine (4.03 g,17.0 mmol), K₂CO₃ (2.40 g, 17.4 mmol) and CuI (179 mg, 0.94 mmol) inDMSO (10 mL) was heated at 100° C. for 12 h. The reaction mixture wascooled to RT, poured into H₂O (ca. 150 mL) and washed with EtOAc (×2).The organic layers were extracted with a small amount of H₂O and thecombined aq phases were acidified to ca. pH 2 with 6N HCl. The volumewas reduced to about one-third and 20 g of cation exchange resin(Strata) was added. The slurry was allowed to stand for 20 min andloaded onto a pad of cation exchange resin (Strata) (ca. 25 g). The padwas washed with H₂O (200 mL), MeOH (200 mL), and then NH₃ (3M in MeOH,2×200 mL). The appropriate fractions was concentrated in vacuo and theresidue (ca. 1.1 g) was dissolved in H₂O, frozen and lyophyllized. Thetitle compound was obtained as a foam (1.02 g, 62%). ¹H NMR (400 MHz,CD₃OD) showed the mixture to contain valine and the purity could not beestimated. The material was used as is in subsequent reactions. LC-MS:Anal. Calcd. for C₉H₁₃N₃O₂: 195; found: 196 (M+H)⁺.

Cap-90

Cap-90 was prepared according to the method described for thepreparation of Cap-1. The crude material was used as is in subsequentsteps. LC-MS: Anal. Calcd. for C₁₁H₁₅NO₂: 193; found: 192 (M−H)⁻.

Cap-91 to Cap-116

The following Caps were prepared according to the method used forpreparation of Cap-51 unless noted otherwise:

Cap Structure LC-MS Cap-91

LC-MS: Anal. Calcd. for C₁₁H₁₃NO₄: 223; found: 222 (M − H)⁻. Cap-92

LC-MS: Anal. Calcd. for C₁₁H₁₃NO₄: 223; found: 222 (M − H)⁻. Cap-93

LC-MS: Anal. Calcd. for C₁₀H₁₂N₂O₄: 224; found: 225 (M + H)⁺. Cap-94

LC-MS: Anal. Calcd. for C₈H₁₁N₃O₄: 213; found: 214 (M + H)⁺. Cap-95

LC-MS: Anal. Calcd. for C₁₃H₁₇NO₄: 251; found: 250 (M − H)⁻. Cap-96

LC-MS: Anal. Calcd. for C₁₂H₁₅NO₄: 237; found: 236 (M − H)⁻. Cap-97

LC-MS: Anal. Calcd. for C₉H₁₅NO₄: 201; found: 200 (M − H)⁻. Cap-98

LC-MS: Anal. Calcd. for C₉H₁₅NO₄: 201; found: 202 (M + H)⁺. Cap-99

¹H NMR (400 MHz, CD₃OD) δ 3.88- 3.94 (m, 1H), 3.60, 3.61 (s, 3H), 2.80(m, 1H), 2.20 (m 1H), 1.82-1.94 (m, 3H), 1.45-1.71 (m, 2H). Cap-99a

¹H NMR (400 MHz, CD₃OD) δ 3.88- 3.94 (m, 1H), 3.60, 3.61 (s, 3H), 2.80(m, 1H), 2.20 (m 1H), 1.82-1.94 (m, 3H), 1.45-1.71 (m, 2H). Cap-100

LC-MS: Anal. Calcd. for C₁₂H₁₄NO₄F: 255; found: 256 (M + H)⁺. Cap-101

LC-MS: Anal. Calcd. for C₁₁H₁₃NO₄: 223; found: 222 (M − H)⁻. Cap-102

LC-MS: Anal. Calcd. for C₁₁H₁₃NO₄: 223; found: 222 (M − H)⁻ Cap-103

LC-MS: Anal. Calcd. for C₁₀H₁₂N₂O₄: 224; found: 225 (M + H)⁺. Cap-104

¹H NMR (400 MHz, CD₃OD) δ 3.60 (s, 3H), 3.50-3.53 (m, 1H), 2.66- 2.69and 2.44-2.49 (m, 1H), 1.91- 2.01 (m, 2H), 1.62-1.74 (m, 4H), 1.51-1.62(m, 2H). Cap-105

¹H NMR (400 MHz, CD₃OD) δ 3.60 (s, 3H), 3.33-3.35 (m, 1H, partiallyobscured by solvent), 2.37-2.41 and 2.16-2.23 (m, 1H), 1.94-2.01 (m,4H), 1.43-1.53 (m, 2H), 1.17-1.29 (m, 2H). Cap-106

¹H NMR (400 MHz, CD₃OD) δ 3.16 (q, J = 7.3 Hz, 4H), 2.38-2.41 (m, 1H),2.28-2.31 (m, 2H), 1.79-1.89 (m, 2H), 1.74 (app, ddd J = 3.5, 12.5, 15.9Hz, 2H), 1.46 (app dt J = 4.0, 12.9 Hz, 2H), 1.26 (t, J = 7.3 Hz, 6H)Cap-107

LC-MS: Anal. Calcd. for C₈H₁₀N₂O₄S: 230; found: 231 (M + H)⁺. Cap-108

LC-MS: Anal. Calcd. for C₁₅H₁₇N₃O₄: 303; found: 304 (M + H)⁺. Cap-109

LC-MS: Anal. Calcd. for C₁₀H₁₂N₂O₄: 224; found: 225 (M + H)⁺. Cap-110

LC-MS: Anal. Calcd. for C₁₀H₁₂N₂O₄: 224; found: 225 (M + H)⁺. Cap-111

LC-MS: Anal. Calcd. for C₁₂H₁₆NO₈P: 333; found: 334 (M + H)⁺. Cap-112

LC-MS: Anal. Calcd. for C₁₃H₁₄N₂O₄: 262; found: 263 (M + H)⁺. Cap-113

LC-MS: Anal. Calcd. for C₁₈H₁₉NO₅: 329; found: 330 (M + H]⁺. Cap-114

¹H NMR (400 MHz, CDCl₃) δ 4.82- 4.84 (m, 1H), 4.00-4.05 (m, 2H), 3.77(s, 3H), 2.56 (s, br, 2H) Cap-115

¹H NMR (400 MHz, CDCl₃) δ 5.13 (s, br, 1H), 4.13 (s, br, 1H), 3.69 (s,3H), 2.61 (d, J = 5.0 Hz, 2H), 1.28 (d, J = 9.1 Hz, 3H). Cap-116

¹H NMR (400 MHz, CDCl₃) δ 5.10 (d, J = 8.6 Hz, 1H), 3.74-3.83 (m, 1H),3.69 (s, 3H), 2.54-2.61 (m, 2H), 1.88 (sept, J = 7.0 Hz, 1H), 0.95 (d, J= 7.0 Hz, 6H).

Cap-117 to Cap-123

For the preparation of Cap-117 to Cap-123 the Boc amino acids wereobtained from commercially sources and were deprotected by treatmentwith 25% TFA in CH₂Cl₂. After complete reaction as judged by LC-MS thesolvents were removed in vacuo and the corresponding TFA salt of theamino acid was carbamoylated with methyl chloroformate according to theprocedure described for Cap-51.

Cap Structure LC-MS Cap-117

LC-MS: Anal. Calcd. for C₁₂H₁₅NO₄: 237; found: 238 (M + H)⁺. Cap-118

LC-MS: Anal. Calcd. for C₁₀H₁₃NO₄S: 243; found: 244 (M + H)⁺. Cap-119

LC-MS: Anal. Calcd. for C₁₀H₁₃NO₄S: 243; found: 244 (M + H)⁺. Cap-120

LC-MS: Anal. Calcd. for C₁₀H₁₃NO₄S: 243; found: 244 (M + H)⁺. Cap-121

¹H NMR (400 MHz, CDCl₃) δ 4.06-4.16 (m, 1H), 3.63 (s, 3H), 3.43 (s, 1H),2.82 and 2.66 (s, br, 1H), 1.86-2.10 (m, 3H), 1.64-1.76 (m, 2H),1.44-1.53 (m, 1H). Cap-122

¹H NMR profile is similar to that of its stereoisomer, Cap-121. Cap-123

LC-MS: Anal. Calcd. for C₂₇H₂₆N₂O₆: 474; found: 475 (M + H)⁺.

Cap-124

The hydrochloride salt of L-threonine tert-butyl ester was carbamoylatedaccording to the procedure for Cap-51. The crude reaction mixture wasacidified with 1N HCl to pH˜1 and the mixture was extracted with EtOAc(2×50 mL). The combined organic phases were concentrated in vacuo togive a colorless oil which solidified on standing. The aqueous layer wasconcentrated in vacuo and the resulting mixture of product and inorganicsalts was triturated with EtOAc—CH₂Cl₂-MeOH (1:1:0.1) and then theorganic phase concentrated in vacuo to give a colorless oil which wasshown by LC-MS to be the desired product. Both crops were combined togive 0.52 g of a solid. ¹H NMR (400 MHz, CD₃OD) δ 4.60 (m, 1H), 4.04 (d,J=5.0 Hz, 1H), 1.49 (d, J=6.3 Hz, 3H). LC-MS: Anal. Calcd. for C₅H₇NO₄:145; found: 146 (M+H)⁺.

Cap-125

To a suspension of Pd(OH)₂, (20%, 100 mg), aqueous formaldehyde (37% wt,4 ml), acetic acid, (0.5 mL) in methanol (15 mL) was added(S)-4-amino-2-(tert-butoxycarbonylamino)butanoic acid (1 g, 4.48 mmol).The reaction was purged several times with hydrogen and was stirredovernight with an hydrogen balloon room temperature. The reactionmixture was filtered through a pad of diatomaceous earth (CELITE®), andthe volatile component was removed in vacuo. The resulting crudematerial was used as is for the next step. LC-MS: Anal. Calcd. forC₁₁H₂₂N₂O₄: 246; found: 247 (M+H)⁺.

Cap-126

This procedure is a modification of that used to prepare Cap-51. To asuspension of 3-methyl-L-histidine (0.80 g, 4.70 mmol) in THF (10 mL)and H₂O (10 mL) at 0° C. was added NaHCO₃ (0.88 g, 10.5 mmol). Theresulting mixture was treated with C1CO₂Me (0.40 mL, 5.20 mmol) and themixture allowed to stir at 0° C. After stirring for ca. 2 h LC-MS showedno starting material remaining. The reaction was acidified to pH 2 with6 N HCl.

The solvents were removed in vacuo and the residue was suspended in 20mL of 20% MeOH in CH₂Cl₂. The mixture was filtered and concentrated togive a light yellow foam (1.21 g). LC-MS and ¹H NMR showed the materialto be a 9:1 mixture of the methyl ester and the desired product. Thismaterial was taken up in THF (10 mL) and H₂O (10 mL), cooled to 0° C.and LiOH (249.1 mg, 10.4 mmol) was added. After stirring ca. 1 h LC-MSshowed no ester remaining. Therefore the mixture was acidified with 6NHCl and the solvents removed in vacuo. LC-MS and ¹H NMR confirm theabsence of the ester. The title compound was obtained as its HCl saltcontaminated with inorganic salts (1.91 g, >100%). The compound was usedas is in subsequent steps without further purification. ¹H NMR (400 MHz,CD₃OD) δ 8.84, (s, 1H), 7.35 (s, 1H), 4.52 (dd, J=5.0, 9.1 Hz, 1H), 3.89(s, 3H), 3.62 (s, 3H), 3.35 (dd, J=4.5, 15.6 Hz, 1H, partially obscuredby solvent), 3.12 (dd, J=9.0, 15.6 Hz, 1H). LC-MS: Anal. Calcd. forC₉H₁₃N₃O₄: 227.09; found: 228.09 (M+H)⁺.

Cap-127

Cap-127 was prepared according to the method for Cap-126 above startingfrom (S)-2-amino-3-(1-methyl-1H-imidazol-4-yl)propanoic acid (1.11 g,6.56 mmol), NaHCO₃ (1.21 g, 14.4 mmol) and C1CO₂Me (0.56 mL, 7.28 mmol).The title compound was obtained as its HCl salt (1.79 g, >100%)contaminated with inorganic salts. LC-MS and ¹H NMR showed the presenceof ca. 5% of the methyl ester. The crude mixture was used as is withoutfurther purification. ¹H NMR (400 MHz, CD₃OD) δ 8.90 (s, 1H), 7.35 (s,1H), 4.48 (dd, J=5.0, 8.6 Hz, 1H), 3.89 (s, 3H), 3.62 (s, 3H), 3.35 (m,1H), 3.08 (m, 1H); LC-MS: Anal. Calcd. for C₉H₁₃N₃O₄: 227.09; found: 228(M+H)⁺.

Preparation of Cap-128

Step 1. Preparation of (S)-benzyl2-(tert-butoxycarbonylamino)pent-4-ynoate (cj-27b)

To a solution of cj-27a (1.01 g, 4.74 mmol), DMAP (58 mg, 0.475 mmol)and iPr₂NEt (1.7 mL, 9.8 mmol) in CH₂Cl₂ (100 mL) at 0° C. was addedCbz-Cl (0.68 mL, 4.83 mmol). The solution was allowed to stir for 4 h at0° C., washed (1N KHSO₄, brine), dried (Na₂SO₄), filtered, andconcentrated in vacuo. The residue was purified by flash columnchromatography (TLC 6:1 hex:EtOAc) to give the title compound (1.30 g,91%) as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 7.35 (s, 5H), 5.35(d, br, J=8.1 Hz, 1H), 5.23 (d, J=12.2 Hz, 1H), 5.17 (d, J=12.2 Hz, 1H),4.48-4.53 (m, 1H), 2.68-2.81 (m, 2H), 2.00 (t, J=2.5 Hz, 1H), 1.44 (s,9H). LC-MS: Anal. Calcd. for C₁₇H₂₁NO₄: 303; found: 304 (M+H)⁺.

Step 2. Preparation of (S)-benzyl3-(1-benzyl-1H-1,2,3-triazol-4-yl)-2-(tert-butoxycarbonylamino)propanoate(cj-28)

To a mixture of (S)-benzyl 2-(tert-butoxycarbonylamino)pent-4-ynoate(0.50 g, 1.65 mmol), sodium ascorbate (0.036 g, 0.18 mmol), CuSO₄-5H₂O(0.022 g, 0.09 mmol) and NaN₃ (0.13 g, 2.1 mmol) in DMF-H₂O (5 mL, 4:1)at rt was added BnBr (0.24 mL, 2.02 mmol) and the mixture was warmed to65° C. After 5 h LC-MS indicated low conversion. A further portion ofNaN₃ (100 mg) was added and heating was continued for 12 h. The reactionwas poured into EtOAc and H₂O and shaken. The layers were separated andthe aqueous layer extracted 3× with EtOAc and the combined organicphases washed (H₂O×3, brine), dried (Na₂SO₄), filtered, andconcentrated. The residue was purified by flash (BIOTAGE®, 40+M 0-5%MeOH in CH₂Cl₂; TLC 3% MeOH in CH₂Cl₂) to afford a light yellow oilwhich solidified on standing (748.3 mg, 104%). The NMR was consistentwith the desired product but suggests the presence of DMF. The materialwas used as is without further purification. ¹H NMR (400 MHz, DMSO-d₆) δ7.84 (s, 1H), 7.27-7.32 (m, 10H), 5.54 (s, 2H), 5.07 (s, 2H), 4.25 (m,1H), 3.16 (dd, J=1.0, 5.3 Hz, 1H), 3.06 (dd, J=5.3, 14.7 Hz), 2.96 (dd,J=9.1, 14.7 Hz, 1H), 1.31 (s, 9H). LC-MS: Anal. Calcd. for C₂₄H₂₈N₄O₄:436; found: 437 (M+H)⁺.

Step 3. Preparation of (S)-benzyl3-(1-benzyl-1H-1,2,3-triazol-4-yl)-2-(methoxycarbonylamino)propanoate(cj-29)

A solution of (S)-benzyl3-(1-benzyl-1H-1,2,3-triazol-4-yl)-2-(tert-butoxycarbonylamino)propanoate(0.52 g, 1.15 mmol) in CH₂Cl₂ was added TFA (4 mL). The mixture wasallowed to stir at room temperature for 2 h. The mixture wasconcentrated in vacuo to give a colorless oil which solidified onstanding. This material was dissolved in THF-H₂O and cooled to 0° C.Solid NaHCO₃ (0.25 g, 3.00 mmol) was added followed by C1CO₂Me (0.25 mL,3.25 mmol). After stirring for 1.5 h the mixture was acidified to pH˜2with 6N HCl and then poured into H₂O-EtOAc. The layers were separatedand the aq phase extracted 2× with EtOAc. The combined org layers werewashed (H₂O, brine), dried (Na₂SO₄), filtered, and concentrated in vacuoto give a colorless oil (505.8 mg, 111%, NMR suggested the presence ofan unidentified impurity) which solidified while standing on the pump.The material was used as is without further purification. ¹H NMR (400MHz, DMSO-d₆) δ 7.87 (s, 1H), 7.70 (d, J=8.1 Hz, 1H), 7.27-7.32 (m,10H), 5.54 (s, 2H), 5.10 (d, J=12.7 Hz, 1H), 5.06 (d, J=12.7 Hz, 1H),4.32-4.37 (m, 1H), 3.49 (s, 3H), 3.09 (dd, J=5.6, 14.7 Hz, 1H), 2.98(dd, J=9.6, 14.7 Hz, 1H). LC-MS: Anal. Calcd. for C₂₁H₂₂N₄O₄: 394;found: 395 (M+H)⁺.

Step 4. Preparation of(S)-2-(methoxycarbonylamino)-3-(1H-1,2,3-triazol-4-yl)propanoic acid(Cap-128)

(S)-Benzyl3-(1-benzyl-1H-1,2,3-triazol-4-yl)-2-(methoxycarbonylamino)propanoate(502 mg, 1.11 mmol) was hydrogenated in the presence of Pd—C (82 mg) inMeOH (5 mL) at atmospheric pressure for 12 h. The mixture was filteredthrough diatomaceous earth (CELITE®) and concentrated in vacuo.(S)-2-(methoxycarbonylamino)-3-(1H-1,2,3-triazol-4-yl)propanoic acid wasobtained as a colorless gum (266 mg, 111%) which was contaminated withca. 10% of the methyl ester. The material was used as is without furtherpurification. ¹H NMR (400 MHz, DMSO-d₆) δ 12.78 (s, br, 1H), 7.59 (s,1H), 7.50 (d, J=8.0 Hz, 1H), 4.19-4.24 (m, 1H), 3.49 (s, 3H), 3.12 (dd,J=4.8 Hz, 14.9 Hz, 1H), 2.96 (dd, J=9.9, 15.0 Hz, 1H). LC-MS: Anal.Calcd. for C₇H₁₀N₄O₄: 214; found: 215 (M+H)⁺.

Preparation of Cap-129

Step 1. Preparation of(S)-2-(benzyloxycarbonylamino)-3-(1H-pyrazol-1-yl)propanoic acid (cj-31)

A suspension of (S)-benzyl 2-oxooxetan-3-ylcarbamate (0.67 g, 3.03mmol), and pyrazole (0.22 g, 3.29 mmol) in CH₃CN (12 mL) was heated at50° C. for 24 h. The mixture was cooled to rt overnight and the solidfiltered to afford(S)-2-(benzyloxycarbonylamino)-3-(1H-pyrazol-1-yl)propanoic acid (330.1mg). The filtrate was concentrated in vacuo and then triturated with asmall amount of CH₃CN (ca. 4 mL) to afford a second crop (43.5 mg).Total yield 370.4 mg (44%). m.p. 165.5-168° C. lit m.p. 168.5-169.5[Vederas et al., J. Am. Chem. Soc., 107:7105 (1985)]. ¹H NMR (400 MHz,CD₃OD) δ 7.51 (d, J=2.0, 1H), 7.48 (s, J=1.5 Hz, 1H), 7.24-7.34 (m, 5H),6.23 m, 1H), 5.05 (d, 12.7; H, 1H), 5.03 (d, J=12.7 Hz, 1H), 4.59-4.66(m, 2H), 4.42-4.49 (m, 1H). LC-MS: Anal. Calcd. for C₁₄H₁₅N₃O₄: 289;found: 290 (M+H)⁺.

Step 2. Preparation of(S)-2-(methoxycarbonylamino)-3-(1H-pyrazol-1-yl)propanoic acid (Cap-129)

(S)-2-(Benzyloxycarbonylamino)-3-(1H-pyrazol-1-yl)propanoic acid (0.20g, 0.70 mmol) was hydrogenated in the presence of Pd—C (45 mg) in MeOH(5 mL) at atmospheric pressure for 2 h. The product appeared to beinsoluble in MeOH, therefore the reaction mixture was diluted with 5 mLH₂O and a few drops of 6N HCl. The homogeneous solution was filteredthrough diatomaceous earth (CELITE®), and the MeOH removed in vacuo. Theremaining solution was frozen and lyophyllized to give a yellow foam(188.9 mg). This material was suspended in THF-H₂O (1:1, 10 mL) and thencooled to 0° C. To the cold mixture was added NaHCO₃ (146.0 mg, 1.74mmol) carefully (evolution of CO₂). After gas evolution had ceased (ca.15 min) ClCO₂Me (0.06 mL, 0.78 mmol) was added dropwise. The mixture wasallowed to stir for 2 h and was acidified to pH˜2 with 6N HCl and pouredinto EtOAc. The layers were separated and the aqueous phase extractedwith EtOAC (×5). The combined organic layers were washed (brine), dried(Na₂SO₄), filtered, and concentrated to give the title compound as acolorless solid (117.8 mg, 79%). ¹H NMR (400 MHz, DMSO-d₆) δ 13.04 (s,1H), 7.63 (d, J=2.6 Hz, 1H), 7.48 (d, J=8.1 Hz, 1H), 7.44 (d, J=1.5 Hz,1H), 6.19 (app t, J=2.0 Hz, 1H), 4.47 (dd, J=3.0, 12.9 Hz, 1H),4.29-4.41 (m, 2H), 3.48 (s, 3H). LC-MS: Anal. Calcd. for C₈H₁₁N₃O₄: 213;found: 214 (M+H)⁺.

Cap-130

Cap-130 was prepared by acylation of commercially available(R)-phenylglycine analogous to the procedure given in: Calmes, M. etal., Tetrahedron, 43(10):2285 (1987).

Cap-131

Step a: Dimethylcarbamoyl chloride (0.92 mL, 10 mmol) was added slowlyto a solution of (S)-benzyl 2-amino-3-methylbutanoate hydrochloride(2.44 g; 10 mmol) and Hunig's base (3.67 mL, 21 mmol) in THF (50 mL).The resulting white suspension was stirred at room temperature overnight(16 hours) and concentrated under reduced pressure. The residue waspartitioned between ethyl acetate and water. The organic layer waswashed with brine, dried (MgSO₄), filtered, and concentrated underreduced pressure. The resulting yellow oil was purified by flashchromatography, eluting with ethyl acetate:hexanes (1:1). Collectedfractions were concentrated under vacuum providing 2.35 g (85%) of clearoil. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.84 (d, J=6.95 Hz, 3H), 0.89 (d,J=6.59 Hz, 3H), 1.98-2.15 (m, 1H), 2.80 (s, 6H), 5.01-5.09 (m, J=12.44Hz, 1H), 5.13 (d, J=12.44 Hz, 1H), 6.22 (d, J=8.05 Hz, 1H), 7.26-7.42(m, 5H). LC (Cond. 1): RT=1.76 min; MS: Anal. Calcd. for [M+H]⁺C₁₆H₂₂N₂O₃: 279.17; found 279.03.

Step b: To an MeOH (50 mL) solution of the intermediate prepared above(2.35 g; 8.45 mmol) was added Pd/C (10%; 200 mg) and the resulting blacksuspension was flushed with N₂ (3×) and placed under 1 atm of H₂. Themixture was stirred at room temperature overnight and filtered though amicrofiber filter to remove the catalyst. The resulting clear solutionwas then concentrated under reduced pressure to obtain 1.43 g (89%) ofCap-131 as a white foam, which was used without further purification. ¹HNMR (500 MHz, DMSO-d₆) δ ppm 0.87 (d, J=4.27 Hz, 3H), 0.88 (d, J=3.97Hz, 3H), 1.93-2.11 (m, 1H), 2.80 (s, 6H), 3.90 (dd, J=8.39, 6.87 Hz,1H), 5.93 (d, J=8.54 Hz, 1H), 12.36 (s, 1H). LC (Cond. 1): RT=0.33 min;MS: Anal. Calcd. for [M+H]⁺ C₈H₁₇N₂O₃: 189.12; found 189.04.

Cap-132

Cap-132 was prepared from (S)-benzyl 2-aminopropanoate hydrochlorideaccording to the method described for Cap-131. ¹H NMR (500 MHz, DMSO-d₆)δ ppm 1.27 (d, J=7.32 Hz, 3H), 2.80 (s, 6H), 4.06 (qt, 1H), 6.36 (d,J=7.32 Hz, 1H), 12.27 (s, 1H). LC (Cond. 1): RT=0.15 min; MS: Anal.Calcd. for [M+H]⁺ C₆H₁₃N₂O₃: 161.09; found 161.00.

Cap-133

Cap-133 was prepared from (S)-tert-butyl 2-amino-3-methylbutanoatehydrochloride and 2-fluoroethyl chloroformate according to the methoddescribed for Cap-47. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.87 (t, J=6.71Hz, 6H), 1.97-2.10 (m, 1H), 3.83 (dd, J=8.39, 5.95 Hz, 1H), 4.14-4.18(m, 1H), 4.20-4.25 (m, 1H), 4.50-4.54 (m, 1H), 4.59-4.65 (m, 1H), 7.51(d, J=8.54 Hz, 1H), 12.54 (s, 1H).

Cap-134

Cap-134 was prepared from (S)-diethyl alanine and methyl chloroformateaccording to the method described for Cap-51. ¹H NMR (500 MHz, DMSO-d₆)δ ppm 0.72-0.89 (m, 6H), 1.15-1.38 (m, 4H), 1.54-1.66 (m, 1H), 3.46-3.63(m, 3H), 4.09 (dd, J=8.85, 5.19 Hz, 1H), 7.24 (d, J=8.85 Hz, 1H), 12.55(s, 1H). LC (Cond. 2): RT=0.66 min; LC-MS: Anal. Calcd. for [M+H]⁺C₉H₁₈NO₄: 204.12; found 204.02.

Cap-135

A solution of D-2-amino-(4-fluorophenyl)acetic acid (338 mg, 2.00 mmol),1N HCl in diethylether (2.0 mL, 2.0 mmol) and formalin (37%, 1 mL) inmethanol (5 mL) was subjected to balloon hydrogenation over 10%palladium on carbon (60 mg) for 16 h at 25° C. The mixture was thenfiltered through CELITE® to afford the HCl salt of Cap-135 as a whitefoam (316 mg, 80%). ¹H NMR (300 MHz, MeOH-d₄) δ 7.59 (dd, J=8.80, 5.10Hz, 2H), 7.29 (t, J=8.6 Hz, 2H), 5.17 (s, 1H), 3.05 (v br s, 3H), 2.63(v br s, 3H); R_(t)=0.19 min (Cond.-MS-WS); 95% homogenity index; LRMS:Anal. Calcd. for [M+H]⁺ C₁₀H₁₃FNO₂: 198.09; found: 198.10.

Cap-136

To a cooled (−50° C.) suspension of 1-benzyl-1H-imidazole (1.58 g, 10.0mmol) in anhydrous diethyl ether (50 mL) under nitrogen was addedn-butyl lithium (2.5 M in hexanes, 4.0 mL, 10.0 mmol) dropwise. Afterbeing stirred for 20 min at −50° C., dry carbon dioxide (passed throughDrierite) was bubbled into the reaction mixture for 10 min before it wasallowed to warm up to 25° C. The heavy precipitate which formed onaddition of carbon dioxide to the reaction mixture was filtered to yielda hygroscopic, white solid which was taken up in water (7 mL), acidifiedto pH=3, cooled, and induced to crystallize with scratching. Filtrationof this precipitate gave a white solid which was suspended in methanol,treated with 1N HCl/diethyl ether (4 mL) and concentrated in vacuo.Lyophilization of the residue from water (5 mL) afforded the HCl salt ofCap-136 as a white solid (817 mg, 40%). ¹H NMR (300 MHz, DMSO-d₆) δ 7.94(d, J=1.5 Hz, 1H), 7.71 (d, J=1.5 Hz, 1H), 7.50-7.31 (m, 5H), 5.77 (s,2H); R_(t)=0.51 min (Cond.-MS-W5); 95% homogenity index; LRMS: Anal.Calc. for [M+H]⁺ C₁₁H₁₂N₂O₂: 203.08; found: 203.11.

Cap-137

Cap-137, Step a

A suspension of 1-chloro-3-cyanoisoquinoline (188 mg, 1.00 mmol;prepared according to the procedure in WO 2003/099274) (188 mg, 1.00mmol), cesium fluoride (303.8 mg, 2.00 mmol),bis(tri-tert-butylphosphine)palladium dichloride (10 mg, 0.02 mmol) and2-(tributylstannyl)furan (378 μL, 1.20 mmol) in anhydrous dioxane (10mL) under nitrogen was heated at 80° C. for 16 h before it was cooled to25° C. and treated with saturated, aqueous potassium fluoride solutionwith vigorous stirring for 1 h. The mixture was partitioned betweenethyl acetate and water and the organic phase was separated, washed withbrine, dried over Na₂SO₄, filtered and concentrated. Purification of theresidue on silica gel (elution with 0% to 30% ethyl acetate/hexanes)afforded Cap-137, Step a as a white solid which was used as is (230 mg,105%). R_(t)=1.95 min (Cond.-MS-W2); 90% homogeneity index; LRMS: Anal.Calc. for [M+H]⁺ C₁₄H₈N₂O: 221.07; found: 221.12.

Cap-137

To a suspension of Cap-137, Step a (110 mg, 0.50 mmol) and sodiumperiodate (438 mg, 2.05 mmol) in carbon tetrachloride (1 mL),acetonitrile (1 mL) and water (1.5 mL) was added ruthenium trichloridehydrate (2 mg, 0.011 mmol). The mixture was stirred at 25° C. for 2 hand then partitioned between dichloromethane and water. The aqueouslayer was separated, extracted twice more with dichloromethane and thecombined dichloromethane extracts were dried over Na₂SO₄, filtered andconcentrated. Trituration of the residue with hexanes afforded Cap-137(55 mg, 55%) as a grayish-colored solid. R_(t)=1.10 min (Cond.-MS-W2);90% homogeneity index; LC-MS: Anal. Calc. for [M+H]⁺C₁₁H₈N₂O₂: 200.08;found: 200.08.

Cap-138 to Cap-158

Synthetic Strategy. Method A.

Cap-138

Cap-138, Step a

To a stirred suspension of 5-hydroxisoquinoline (prepared according tothe procedure in WO 2003/099274) (2.0 g, 13.8 mmol) andtriphenylphosphine (4.3 g, 16.5 mmol) in dry tetrahydrofuran (20 mL) wasadded dry methanol (0.8 mL) and diethyl azodicarboxylate (3.0 mL, 16.5mmol) portionwise. The mixture was stirred at room temperature for 20 hbefore it was diluted with ethyl acetate and washed with brine, driedover Na₂SO₄, filtered and concentrated. The residue was preabsorbed ontosilica gel and purified (elution with 40% ethyl acetate/hexanes) toafford Cap-138, Step a as a light yellow solid (1.00 g, 45%). ¹H NMR(CDCl₃, 500 MHz) δ 9.19 (s, 1H), 8.51 (d, J=6.0 Hz, 1H), 7.99 (d, J=6.0Hz, 1H), 7.52-7.50 (m, 2H), 7.00-6.99 (m, 1H), 4.01 (s, 3H); R_(t)=0.66min (Cond. D2); 95% homogeneity index; LC-MS: Anal. Calc. for [M+H]⁺C₁₀H₁₀NO: 160.08; found 160.10.

Cap-138, Step b

To a stirred solution of Cap-138, Step a (2.34 g, 14.7 mmol) inanhydrous dichloromethane (50 mL) at room temperature was addedmeta-chloroperbenzoic acid (77%, 3.42 g, 19.8 mmol) in one portion.After being stirred for 20 h, powdered potassium carbonate (2.0 g) wasadded and the mixture was stirred for 1 h at room temperature before itwas filtered and concentrated to afford Cap-138, Step b as a pale,yellow solid which was sufficiently pure to carry forward (2.15 g,83.3%). ¹H NMR (CDCl₃, 400 MHz) δ 8.73 (d, J=1.5 Hz, 1H), 8.11 (dd,J=7.3, 1.7 Hz, 1H), 8.04 (d, J=7.1 Hz, 1H), 7.52 (t, J=8.1 Hz, 1H), 7.28(d, J=8.3 Hz, 1H), 6.91 (d, J=7.8 Hz, 1H), 4.00 (s, 3H); R_(t)=0.92 min,(Cond.-D1); 90% homogenity index; LC-MS: Anal. Calc. for [M+H]⁺C₁₀H₁₀NO₂: 176.07; found: 176.0.

Cap-138, Step c

To a stirred solution of Cap-138, Step b (0.70 g, 4.00 mmol) andtriethylamine (1.1 mL, 8.00 mmol) in dry acetonitrile (20 mL) at roomtemperature under nitrogen was added trimethylsilylcyanide (1.60 mL,12.00 mmol). The mixture was heated at 75° C. for 20 h before it wascooled to room temperature, diluted with ethyl acetate and washed withsaturated sodium bicarbonate solution and brine prior to drying overNa₂SO₄ and solvent concentration. The residue was flash chromatographedon silica gel (elution with 5% ethyl acetate/hexanes) to 25% ethylacetate/hexanes to afford Cap-138, Step c (498.7 mg) as a white,crystalline solid along with 223 mg of additional Cap-138, Step crecovered from the filtrate. ¹H NMR (CDCl₃, 500 MHz) δ 8.63 (d, J=5.5Hz, 1H), 8.26 (d, J=5.5 Hz, 1H), 7.88 (d, J=8.5 Hz, 1H), 7.69 (t, J=8.0Hz, 1H), 7.08 (d, J=7.5 Hz, 1H), 4.04 (s, 3H); R_(t)=1.75 min,(Cond.-D1); 90% homogeneity index; LC-MS: Anal. Calc. for [M+H]⁺C₁₁H₉N₂O: 185.07; found: 185.10.

Cap-138

Cap-138, Step c (0.45 g, 2.44 mmol) was treated with 5N sodium hydroxidesolution (10 mL) and the resulting suspension was heated at 85° C. for 4h, cooled to 25° C., diluted with dichloromethane and acidified with 1Nhydrochloric acid. The organic phase was separated, washed with brine,dried over Na₂SO₄, concentrated to ¼ volume and filtered to affordCap-138 as a yellow solid (0.44 g, 88.9%). ¹H NMR (DMSO-d₆, 400 MHz) δ13.6 (br s, 1H), 8.56 (d, J=6.0 Hz, 1H), 8.16 (d, J=6.0 Hz, 1H), 8.06(d, J=8.8 Hz, 1H), 7.71-7.67 (m, 1H), 7.30 (d, J=8.0 Hz, 1H), 4.02 (s,3H); R_(t)=0.70 min (Cond.-D1); 95% homogenity index; LC-MS: Anal. Calc.for [M+H]⁺ C₁₁H₁₀NO₃: 204.07; found: 204.05.

Synthetic Strategy. Method B (Derived from Tetrahedron Letters, 42:6707(2001)).

Cap-139

Cap-139, Step a

To a thick-walled, screw-top vial containing an argon-degassedsuspension of 1-chloro-6-methoxyisoquinoline (1.2 g, 6.2 mmol; preparedaccording to the procedure in WO 2003/099274), potassium cyanide (0.40g, 6.2 mmol), 1,5-bis(diphenylphosphino)pentane (0.27 g, 0.62 mmol) andpalladium (II) acetate (70 mg, 0.31 mmol) in anhydrous toluene (6 mL)was added N,N,N′,N′-tetramethylethylenediamine (0.29 mL, 2.48 mmol). Thevial was sealed, heated at 150° C. for 22 h and then allowed to cool to25° C. The reaction mixture was diluted with ethyl acetate, washed withwater and brine, dried over Na₂SO₄, filtered and concentrated. Theresidue was purified on silica gel eluting with 5% ethyl acetate/hexanesto 25% ethyl acetate/hexanes to afford Cap-139, Step a as a white solid(669.7 mg). ¹H NMR (CDCl₃, 500 MHz) δ 8.54 (d, J=6.0 Hz, 1H), 8.22 (d,J=9.0 Hz, 1H), 7.76 (d, J=5.5 Hz, 1H), 7.41-7.39 (m, 1H), 7.13 (d, J=2.0Hz, 1H), 3.98 (s, 3H); R_(t)=1.66 min (Cond.-D1); 90% homogenity index;LC-MS: Anal. Calc. for [M+H]⁺ C₁₁H₉N₂O: 185.07; found: 185.20.

Cap-139

Cap-139 was prepared from the basic hydrolysis of Cap-139, Step a with5N NaOH according to the procedure described for Cap-138. ¹H NMR (400MHz, DMSO-d₆) δ 13.63 (v br s, 1H), 8.60 (d, J=9.3 Hz, 1H), 8.45 (d,J=5.6 Hz, 1H), 7.95 (d, J=5.9 Hz, 1H), 7.49 (d, J=2.2 Hz, 1H), 7.44 (dd,J=9.3, 2.5 Hz, 1H), 3.95 (s, 3H); R_(t)=0.64 min (Cond.-D1); 90%homogenity index; LC-MS: Anal. Calc. for [M+H]⁺ C₁₁H₁₀NO₃: 204.07;found: 204.05.

Cap-140

Cap-140, Step a

To a vigorously-stirred mixture of 1,3-dichloro-5-ethoxyisoquinoline(482 mg, 2.00 mmol; prepared according to the procedure in WO2005/051410), palladium (II) acetate (9 mg, 0.04 mmol), sodium carbonate(223 mg, 2.10 mmol) and 1,5-bis(diphenylphosphino)pentane (35 mg, 0.08mmol) in dry dimethylacetamide (2 mL) at 25° C. under nitrogen was addedN,N,N′,N′-tetramethylethylenediamine (60 mL, 0.40 mmol). After 10 min,the mixture was heated to 150° C., and then a stock solution of acetonecyanohydrin (prepared from 457 μL of acetone cyanohydrin in 4.34 mL DMA)was added in 1 mL portions over 18 h using a syringe pump. The mixturewas then partitioned between ethyl acetate and water and the organiclayer was separated, washed with brine, dried over Na₂SO₄, filtered andconcentrated. The residue was purified on silica gel eluting with 10%ethyl acetate/hexanes to 40% ethyl acetate/hexanes to afford Cap-140,Step a as a yellow solid (160 mg, 34%). R_(t)=2.46 min (Cond.-MS-W2);90% homogenity index; LC-MS: Anal. Calc. for [M+H]⁺ C₁₂H₉ClN₂O: 233.05;found: 233.08.

Cap-140

Cap-140 was prepared by the acid hydrolysis of Cap-140, Step a with 12NHCl as described in the procedure for the preparation of Cap-141,described below. R_(t)=2.24 min (Cond.-MS-W2); 90% homogenity index;LC-MS: Anal. Calc. for [M+H]⁺ C₁₂H₁₁ClNO₃: 252.04; found: 252.02.

Cap-141

Cap-141, Step a

Cap-141, Step a was prepared from 1-bromo-3-fluoroisoquinoline (preparedfrom 3-amino-1-bromoisoquinoline using the procedure outlined in J. Med.Chem., 13:613 (1970)) as described in the procedure for the preparationof Cap-140, Step a (vide supra). ¹H NMR (500 MHz, CDCl₃) δ 8.35 (d,J=8.5 Hz, 1H), 7.93 (d, J=8.5 Hz, 1H), 7.83 (t, J=7.63 Hz, 1H),7.77-7.73 (m, 1H), 7.55 (s, 1H); R_(t)=1.60 min (Cond.-D1); 90%homogenity index; LC-MS: Anal. Calc. for [M+H]⁺ C₁₀H₆FN₂: 173.05; found:172.99.

Cap-141

Cap-141, Step a (83 mg, 0.48 mmol) was treated with 12N HCl (3 mL) andthe resulting slurry was heated at 80° C. for 16 h before it was cooledto room temperature and diluted with water (3 mL). The mixture wasstirred for 10 min and then filtered to afford Cap-141 as an off-whitesolid (44.1 mg, 47.8%). The filtrate was diluted with dichloromethaneand washed with brine, dried over Na₂SO₄, and concentrated to affordadditional Cap-141 which was sufficiently pure to be carried forwarddirectly (29.30 mg, 31.8%). ¹H NMR (DMSO-d₆, 500 MHz) δ 14.0 (br s, 1H),8.59-8.57 (m, 1H), 8.10 (d, J=8.5 Hz, 1H), 7.88-7.85 (m, 2H), 7.74-7.71(m, 1H); R_(t)=1.33 min (Cond.-D1); 90% homogenity index; LC-MS: Anal.Calc. for [M+H]⁺ C₁₀H₂FNO₂: 192.05; found: 191.97.

Cap-142

Cap-142, Step a

Cap-142, Step a was prepared from 4-bromoisoquinoline N-oxide asdescribed in the two-step procedure for the preparation of Cap-138,steps b and c. R_(t)=1.45 min (Cond.-MS-W1); 90% homogenity index;LC-MS: Anal. Calc. for [M+H]⁺ C₁₀H₆BrN₂: 232.97; found: 233.00.

Cap-142, Step b

To an argon-degassed suspension of Cap-142, Step a (116 mg, 0.50 mmol),potassium phosphate tribasic (170 mg, 0.80 mmol), palladium (II) acetate(3.4 mg, 0.015 mmol) and 2-(dicyclohexylphosphino)biphenyl (11 mg, 0.03mmol) in anhydrous toluene (1 mL) was added morpholine (61 μL, 0.70mmol). The mixture was heated at 100° C. for 16 h, cooled to 25° C. andfiltered through diatomaceous earth (CELITE®). Purification of theresidue on silica gel, eluting with 10% to 70% ethyl acetate/hexanesafforded Cap-142, Step b (38 mg, 32%) as a yellow solid, which wascarried forward directly. R_(t)=1.26 min (Cond.-MS-W1); 90% homogenityindex; LC-MS: Anal. Calc. for [M+H]⁺ C₁₄H₁₄N₃O: 240.11; found: 240.13.

Cap-142

Cap-142 was prepared from Cap-142, Step b with 5N sodium hydroxide asdescribed in the procedure for Cap-138. R_(t)=0.72 min (Cond.-MS-W1);90% homogenity index; LC-MS: Anal. Calc. for [M+H]⁺ C₁₄H₁₅N₂O₃: 259.11;found: 259.08.

Cap-143

Cap-143, Step a

To a stirred solution of 3-amino-1-bromoisoquinoline (444 mg, 2.00 mmol)in anhydrous dimethylformamide (10 mL) was added sodium hydride (60%,unwashed, 96 mg, 2.4 mmol) in one portion. The mixture was stirred at25° C. for 5 min before 2-bromoethyl ether (90%, 250 μL, 2.00 mmol) wasadded. The mixture was stirred further at 25° C. for 5 h and at 75° C.for 72 h before it was cooled to 25° C., quenched with saturatedammonium chloride solution and diluted with ethyl acetate. The organiclayer was separated, washed with water and brine, dried over Na₂SO₄,filtered and concentrated. Purification of the residue on silica geleluting with 0% to 70% ethyl acetate/hexanes afforded Cap-143, Step a asa yellow solid (180 mg, 31%). R_(t)=1.75 min (Cond.-MS-W1); 90%homogenity index; LC-MS: Anal. Calc. for [M+H]⁺ C₁₃H₁₄BrN₂O: 293.03;found: 293.04.

Cap-143

To a cold (−60° C.) solution of Cap-143, Step a (154 mg, 0.527 mmol) inanhydrous tetrahydrofuran (5 mL) was added a solution of n-butyllithiumin hexanes (2.5 M, 0.25 mL, 0.633 mmol). After 10 min, dry carbondioxide was bubbled into the reaction mixture for 10 min before it wasquenched with 1N HCl and allowed to warm to 25° C. The mixture was thenextracted with dichloromethane (3×30 mL) and the combined organicextracts were concentrated in vacuo. Purification of the residue by areverse phase HPLC (MeOH/water/TFA) afforded Cap-143 (16 mg, 12%).R_(t)=1.10 min (Cond.-MS-W1); 90% homogenity index; LC-MS: Anal. Calc.for [M+H]⁺ C₁₄H₁₅N₂O₃: 259.11; found: 259.08.

Cap-144

Cap-144, Step a

1,3-Dichloroisoquinoline (2.75 g, 13.89 mmol) was added in smallportions to a cold (0° C.) solution of fuming nitric acid (10 mL) andconcentrated sulfuric acid (10 mL). The mixture was stirred at 0° C. for0.5 h before it was gradually warmed to 25° C. where it stirred for 16h. The mixture was then poured into a beaker containing chopped ice andwater and the resulting suspension was stirred for 1 h at 0° C. beforeit was filtered to afford Cap-144, Step a (2.73 g, 81%) as a yellowsolid which was used directly. R_(t)=2.01 min. (Cond.-D1); 95%homogenity index; LC-MS: Anal. Calc. for [M+H]⁺ C₉H₅Cl₂N₂O₂: 242.97;found: 242.92.

Cap-144, Step b

Cap-144, Step a (0.30 g, 1.23 mmol) was taken up in methanol (60 mL) andtreated with platinum oxide (30 mg), and the suspension was subjected toParr hydrogenation at 7 psi H₂ for 1.5 h. Then formalin (5 mL) andadditional platinum oxide (30 mg) were added, and the suspension wasresubjected to Parr hydrogenation at 45 psi H₂ for 13 h. It was thensuction-filtered through diatomaceous earth (CELITE®) and concentrateddown to ¼ volume. Suction-filtration of the ensuing precipitate affordedthe title compound as a yellow solid which was flash chromatographed onsilica gel eluting with 5% ethyl acetate in hexanes to 25% ethyl acetatein hexanes to afford Cap-144, Step b (231 mg, 78%) as a pale yellowsolid. R_(t)=2.36 min (Cond.-D1); 95% homogenity index; ¹H NMR (400 MHz,CDCl₃) δ 8.02 (s, 1H), 7.95 (d, J=8.6 Hz, 1H), 7.57-7.53 (m, 1H), 7.30(d, J=7.3 Hz, 1H), 2.88 (s, 6H); LC-MS: Anal. Calc. for [M+H]⁺C₁₁H₁₁Cl₂N₂: 241.03; found: 241.02. HRMS: Anal. Calc. for [M+H]⁺C₁₁H₁₁Cl₂N₂: 241.0299; found: 241.0296.

Cap-144, Step c

Cap-144, Step c was prepared from Cap-144, Step b according to theprocedure described for the preparation of Cap-139, Step a. R_(t)=2.19min (Cond.-D1); 95% homogenity index; LC-MS: Anal. Calc. for [M+H]⁺C₁₂H₁₁ClN₃: 232.06. found: 232.03. HRMS: Anal. Calc. for [M+H]⁺C₁₂H₁₁ClN₃: 232.0642; found: 232.0631.

Cap-144

Cap-144 was prepared according to the procedure described for Cap-141.R_(t)=2.36 min (Cond.-D1); 90%; LC-MS: Anal. Calc. for [M+H]⁺C₁₂H₁₂ClN₂O₂: 238.01; found: 238.09.

Cap-145 to Cap-162

Cap-145 to Cap-162 were prepared from the appropriate1-chloroisoquinolines according to the procedure described for thepreparation of Cap-138 (Method A) or Cap-139 (Method B) unless notedotherwise as outlined below.

R_(t) (LC- Cond.); % homogeneity index; MS Cap-# Cap Method Hydrolysisdata Cap-145

  Prepared from commercially available 1,3-dichloroisoquinoline B 12NHCl 1.14 min (Cond.-MS- W1); 90%; LC-MS: Anal. Calc. for [M + H]⁺C₁₀H₇ClNO₂: 208.02; found: 208.00. Cap-146

  Prepared from commercially available 3-hydroxyisoquinoline A 5N NaOH1.40 min (Cond.-D1); 95%; LC-MS: Anal. Calc. for [M + H]⁺ C₁₁H₁₀NO₃:204.07; found: 204.06. Cap-147

  Prepared from commercially available 1-chloro-4- hydroxyisoquinoline B5N NaOH 0.87 min (Cond.-D1); 95%; LC-MS: Anal. Calc. for [M + H]⁺C₁₁H₁₀NO₃: 204.07; found: 204.05. Cap-148

  Prepared from commercially available 7-hydroxyisoquinoline A 5N NaOH0.70 min (Cond.-D1); 95%; LC-MS: Anal. Calc. for [M + H]⁺ C₁₁H₁₀NO₃:204.07; found: 204.05. Cap-149

  Prepared from commercially available 5-hydroxyisoquinoline A 5N NaOH0.70 min (Cond.-D1); 95%; LC-MS: Anal. Calc. for [M + H]⁺ C₁₁H₁₀NO₃:204.07; found: 204.05. Cap-150

  Prepared from 8- methoxy-1- chloroisoquinoline, which can besynthesized following the procedure in WO 2003/099274 A 12N HCl 0.26 min(Cond.-D1); 95%; LC-MS: Anal. Calc. for [M + H]⁺ C₁₁H₁₀NO₃: 204.07;found: 204.04. Cap-151 3-chloro-5- methoxyisoquinoline- 1-carboxylicacid

  Prepared from 5- methoxy-1,3- dichloroisoquinoline, which can besynthesized following the procedure in WO 2005/051410 B 12N HCl 1.78 min(Cond.-D1); 90%; LC-MS: Anal. Calc. for [M + H]⁺ C₁₁H₉ClNO₃: 238.03;found: 238.09. Cap-152

  Prepared from commercially available 6-methoxy-1,3-dichloroisoquinoline B 12N HCl 1.65 min (Cond.-D1); 95%; LC-MS: Anal.Calc. for [M + H]⁺ C₁₁H₉ClNO₃: 238.00; found: 238.09. Cap-153

  Prepared from 4- bromoisoquinoline, which can be synthesized followingthe procedure in WO 2003/062241 A 6N HCl 1.18 min (Cond.-MS- W1); 95%;LC-MS: Anal. Calc. for [M + H]⁺ C₁₀H₇BrNO₂: 251.97; found: 251.95.Cap-154

  Prepared from 7-fluoro- 1-chloroisoquinoline, which can be synthesizedfollowing the procedure in WO 2003/099274 B 5N NaOH 0.28 min (Cond.-MS-W1); 90%; LC-MS: Anal. Calc. for [M + H]⁺ C₁₀H₇FNO₂: 192.05; found:192.03. Cap-155

  Prepared from 1,7- dichloroisoquinoline, which can be synthesizedfollowing the procedure in WO 2003/099274 B 5N NaOH 0.59 min (Cond.-MS-W1); 90%; LC-MS: Anal. Calc. for [M + H]⁺ C₁₀H₇ClNO₂: 208.02; found:208.00. Cap-156

  Prepared from 1,6- dichloroisoquinoline, which can be synthesizedfollowing the procedure in WO 2003/099274 B 5N NaOH 0.60 min (Cond.-MS-W1); 90%; LC-MS: Anal. Calc. for [M + H]⁺ C₁₀H₇ClNO₂: 208.02; found:208.03. Cap-157

  Prepared from 1,4- dichloroisoquinoline, which can be synthesizedfollowing the procedure in WO 2003/062241 B 12N HCl 1.49 min (Cond.-D1);95%; LC-MS: Anal. Calc. for [M + H]⁺ C₁₀H₁₇ClNO: 208.02; found: 208.00.Cap-158

  Prepared from 1,5- dichloroisoquinoline, which can be synthesizedfollowing the procedure in WO 2003/099274 B 5N NaOH 0.69 min (Cond.-MS-W1); 90%; LC-MS: Anal. Calc. for [M + H]⁺ C₁₀H₇ClNO₂: 208.02; found:208.01. Cap-159

  Prepared from 5-fluoro- 1-chloroisoquinoline, which can be synthesizedfollowing the procedure in WO 2003/099274 B 5N NaOH 0.41 min (Cond.-MS-W1); 90%; LC-MS: Anal. Calc. for [M + H]⁺ C₁₀H₇FNO₂: 192.05; found:192.03. Cap-160

  Prepared from 6-fluoro- 1-chloroisoquinoline, which can be synthesizedfollowing the procedure in WO 2003/099274 B 5N NaOH 0.30 min (Cond.-MS-W1); 90%; LC-MS: Anal. Calc. for [M + H]⁺ C₁₀H₇FNO₂: 192.05; found:192.03. Cap-161

  Prepared from 4- bromoquinoline-2- carboxylic acid and dimethylamine(DMSO, 100° C.) — — 0.70 min (Cond. D1); 95%; LC-MS: Anal. Calc. for[M + H]⁺ C₁₂H₁₃N₂O₂: 217.10; found: 217.06. Cap-162

  Prepared from m- anisidine following the procedure described in J.Hetero. Chem., 17 (1993) and Heterocycles, 60:953 (2003). — — 0.65 min(Cond.-M3); 95%; LC-MS: Anal. Calc. for [M + H]⁺ C₁₀H₁₀NO₃: 204.07;found: 203.94.

Cap-163

To a solution of 2-ketobutyric acid (1.0 g, 9.8 mmol) in diethylether(25 ml) was added phenylmagnesium bromide (22 ml, 1M in THF) dropwise.The reaction was stirred at ˜25° C. under nitrogen for 17.5 h. Thereaction was acidified with 1N HCl and the product was extracted withethyl acetate (3×100 ml). The combined organic layer was washed withwater followed by brine and dried over MgSO₄. After concentration invacuo, a white solid was obtained. The solid was recrystallized fromhexanes/ethyl acetate to afford Cap-163 as white needles (883.5 mg). ¹HNMR (DMSO-d₆, δ=2.5 ppm, 500 MHz): 12.71 (br s, 1 H), 7.54-7.52 (m, 2H),7.34-7.31 (m, 2H), 7.26-7.23 (m, 1H), 5.52-5.39 (br s, 1H), 2.11 (m,1H), 1.88 (m, 1H), 0.79 (app t, J=7.4 Hz, 3H).

Cap-164

A mixture of 2-amino-2-phenylbutyric acid (1.5 g, 8.4 mmol),formaldehyde (14 mL, 37% in water), 1N HCl (10 mL) and 10% Pd/C (0.5 mg)in MeOH (40 mL) was exposed to H₂ at 50 psi in a Parr bottle for 42 h.The reaction was filtered over CELITE® and concentrated in vacuo, theresidue was taken up in MeOH (36 mL) and the product was purified with areverse phase HPLC (MeOH/H₂O/TFA) to afford the TFA salt of Cap-164 as awhite solid (1.7 g). ¹H NMR (DMSO-d₆, δ=2.5 ppm, 500 MHz) 7.54-7.47 (m,5H), 2.63 (m, 1H), 2.55 (s, 6H), 2.31 (m, 1H), 0.95 (app t, J=7.3 Hz,3H).

Cap-165

To a mixture of 2-amino-2-indanecarboxylic acid (258.6 mg, 1.46 mmol)and formic acid (0.6 ml, 15.9 mmol) in 1,2-dichloroethane (7 ml) wasadded formaldehyde (0.6 ml, 37% in water). The mixture was stirred at˜25° C. for 15 min then heated at 70° C. for 8 h. The volatile componentwas removed in vacuo, and the residue was dissolved in DMF (14 mL) andpurified by a reverse phase HPLC (MeOH/H₂O/TFA) to afford the TFA saltof Cap-165 as a viscous oil (120.2 mg). ¹H NMR (DMSO-d₆, δ=2.5 ppm, 500MHz): 7.29-7.21 (m, 4 H), 3.61 (d, J=17.4 Hz, 2H), 3.50 (d, J=17.4 Hz,2H), 2.75 (s, 6H). LC-MS: Anal. Calcd. for [M+H]⁺ C₁₂H₁₆NO₂: 206.12;found: 206.07.

Cap-166a and Cap-166b

Cap-166a and Cap-166b were prepared from(1S,4S)-(+)-2-methyl-2,5-diazabicyclo[2.2.1]heptane (2HBr) according tothe method described for the synthesis of Cap-7a and Cap-7b, with theexception that the benzyl ester intermediate was separated using asemi-prep Chrialcel OJ column, 20×250 mm, 10 μm eluting with 85:15heptane/ethanol mixture at 10 mL/min elution rate for 25 min. Cap-166b:¹H NMR (DMSO-d₆, δ=2.5 ppm, 500 MHz): 7.45 (d, J=7.3 Hz, 2H), 7.27-7.19(m, 3H), 4.09 (s, 1H), 3.34 (app br s, 1H), 3.16 (app br s, 1H), 2.83(d, J=10.1 Hz, 1H), 2.71 (m, 2H), 2.46 (m, 1H), 2.27 (s, 3H), 1.77 (d,J=9.8 Hz, 1H), 1.63 (d, J=9.8 Hz, 1H). LC-MS: Anal. Calcd. for [M+H]⁺C₁₄H₁₉N₂O₂: 247.14; found: 247.11.

Cap-167

A solution of racemic Boc-1,3-dihydro-2H-isoindole carboxylic acid (1.0g, 3.8 mmol) in 20% TFA/CH₂Cl₂ was stirred at ˜25° C. for 4 h. All thevolatile component was removed in vacuo. A mixture of the resultantcrude material, formaldehyde (15 mL, 37% in water), 1N HCl (10 mL) and10% Pd/C (10 mg) in MeOH was exposed to H₂ (40 PSI) in a Parr bottle for23 h. The reaction mixture was filtered over CELITE® and concentrated invacuo to afford Cap-167 as a yellow foam (873.5 mg). ¹H NMR (DMSO-d₆,δ=2.5 ppm, 500 MHz) 7.59-7.38 (m, 4H), 5.59 (s, 1H), 4.84 (d, J=14 Hz,1H), 4.50 (d, J=14.1 Hz, 1H), 3.07 (s, 3H). LC-MS: Anal. Calcd. for[M+H]⁺ C₁₀H₁₂NO₂: 178.09; found: 178.65.

Cap-168

Racemic Cap-168 was prepared from racemic Boc-aminoindane-1-carboxylicacid according to the procedure described for the preparation ofCap-167. The crude material was employed as such.

Cap-169

A mixture of 2-amino-2-phenylpropanoic acid hydrochloride (5.0 g, 2.5mmol), formaldehyde (15 ml, 37% in water), 1N HCl (15 ml), and 10% Pd/C(1.32 g) in MeOH (60 mL) was placed in a Parr bottle and shaken underhydrogen (55 PSI) for 4 days. The reaction mixture was filtered overCELITE® and concentrated in vacuo. The residue was taken up in MeOH andpurified by reverse phase prep-HPLC (MeOH/water/TFA) to afford the TFAsalt of Cap-169 as a viscous semi-solid (2.1 g). ¹H NMR (CDCl₃, δ=7.26ppm, 500 MHz): 7.58-7.52 (m, 2H), 7.39-7.33 (m, 3H), 2.86 (br s, 3H),2.47 (br s, 3H), 1.93 (s, 3H). LC-MS: Anal. Calcd. for [M+H]⁺ C₁₁H₁₆NO₂:194.12; found: 194.12.

Cap-170

(S)-2-(Methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid

To (S)-2-amino-2-(tetrahydro-2H-pyran-4-yl)acetic acid (505 mg; 3.18mmol; obtained from Astatech) in water (15 ml) was added sodiumcarbonate (673 mg; 6.35 mmol), and the resultant mixture was cooled to0° C. and then methyl chloroformate (0.26 ml; 3.33 mmol) was addeddropwise over 5 minutes. The reaction was allowed to stir for 18 hourswhile allowing the bath to thaw to ambient temperature. The reactionmixture was then partitioned between 1N HCl and ethyl acetate. Theorganic layer was removed and the aqueous layer was further extractedwith 2 additional portions of ethyl acetate. The combined organic layerswere washed with brine, dried over magnesium sulfate, filtered andconcentrated in vacuo to afford Cap-170 a colorless residue. ¹H NMR (500MHz, DMSO-d₆) δ ppm 12.65 (1 H, br s), 7.44 (1 H, d, J=8.24 Hz),3.77-3.95 (3 H, m), 3.54 (3 H, s), 3.11-3.26 (2 H, m), 1.82-1.95 (1 H,m), 1.41-1.55 (2 H, m), 1.21-1.39 (2 H, m); LC-MS: Anal. Calcd. for[M+H]⁺ C₉H₁₆NO₅: 218.1; found 218.1.

Cap-171

A solution of methyl2-(benzyloxycarbonylamino)-2-(oxetan-3-ylidene)acetate (200 mg, 0.721mmol; Il Farmaco, 56:609-613 (2001)) in ethyl acetate (7 ml) and CH₂Cl₂(4.00 ml) was degassed by bubbling nitrogen for 10 min. Dimethyldicarbonate (0.116 ml, 1.082 mmol) and Pd/C (20 mg, 0.019 mmol) werethen added, the reaction mixture was fitted with a hydrogen balloon andallowed to stir at ambient temperature overnight at which time TLC (95:5CH₂Cl₂/MeOH: visualized with stain made from 1 g Ce(NH₄)₂SO₄, 6 gammonium molybdate, 6 ml sulfuric acid, and 100 ml water) indicatedcomplete conversion. The reaction was filtered through CELITE® andconcentrated. The residue was purified via BIOTAGE® (load withdichloromethane on 25 samplet; elute on 25S column with dichloromethanefor 3CV then 0 to 5% MeOH/dichloromethane over 250 ml then hold at 5%MeOH/dichloromethane for 250 ml; 9 ml fractions). Collected fractionscontaining desired material and concentrated to 120 mg (81%) of methyl2-(methoxycarbonylamino)-2-(oxetan-3-yl)acetate as a colorless oil. ¹HNMR (500 MHz, chloroform-d) δ ppm 3.29-3.40 (m, J=6.71 Hz, 1 H) 3.70 (s,3 H) 3.74 (s, 3 H) 4.55 (t, J=6.41 Hz, 1 H) 4.58-4.68 (m, 2 H) 4.67-4.78(m, 2 H) 5.31 (br s, 1 H). LC-MS: Anal. Calcd. for [M+H]⁺ C₈H₁₄NO₅:204.2; found 204.0.

To methyl 2-(methoxycarbonylamino)-2-(oxetan-3-yl)acetate (50 mg, 0.246mmol) in THF (2 mL) and water (0.5 mL) was added lithium hydroxidemonohydrate (10.33 mg, 0.246 mmol). The resultant solution was allowedto stir overnight at ambient temperature. TLC (1:1 EA/Hex; Hanessianstain [1 g Ce(NH₄)₂SO₄, 6 g ammonium molybdate, 6 ml sulfuric acid, and100 ml water]) indicated ˜10% starting material remaining. Added anadditional 3 mg LiOH and allowed to stir overnight at which time TLCshowed no starting material remaining. Concentrated in vacuo and placedon high vac overnight providing 55 mg lithium2-(methoxycarbonylamino)-2-(oxetan-3-yl)acetate as a colorless solid. ¹HNMR (500 MHz, MeOD) δ ppm 3.39-3.47 (m, 1 H) 3.67 (s, 3 H) 4.28 (d,J=7.93 Hz, 1 H) 4.64 (t, J=6.26 Hz, 1 H) 4.68 (t, J=7.02 Hz, 1 H) 4.73(d, J=7.63 Hz, 2 H).

Cap-172

Cap-172, Step a

The following diazotization step was adapted from Barton, A. et al.,J.C.S. Perkin Trans I, 159-164 (1982): A solution of NaNO₂ (166 mg, 2.4mmol) in water (0.6 mL) was added slowly to a stirred, cold (0° C.)solution of methyl 2-amino-5-ethyl-1,3-thiazole-4-carboxylate (186 mg,1.0 mmol), CuSO₄.5H₂O (330 mg, 1.32 mmol), NaCl (260 mg, 4.45 mmol) andH₂SO₄ (5.5 mL) in water (7.5 mL). The mixture was stirred at 0° C. for45 min and allowed to warm up to room temperature where it stirredfurther for 1 h before CuCl (118 mg) was added. This mixture was stirredfurther at room temperature for 16 h before it was diluted with brineand extracted with ether twice. The organic layers were combined, driedover MgSO₄ and concentrated to give methyl2-chloro-5-ethylthiazole-4-carboxylate (i.e., Cap-172, Step a) (175 mg,85%) as an orange oil (80% pure) which was used directly in the nextreaction. R_(t)=1.99 min (Cond.-MD1); LC-MS: Anal. Calcd. for [M+H]⁺C₇H₉ClNO₂S: 206.01; found: 206.05.

Cap-172

To a solution of methyl 2-chloro-5-ethylthiazole-4-carboxylate (175 mg)in THF/H₂O/MeOH (20 mL/3 mL/12 mL) was added LiOH (305 mg, 12.76 mmol).The mixture was stirred at room temperature overnight before it wasconcentrated down and neutralized with 1N HCl in ether (25 mL). Theresidue was extracted twice with ethyl acetate and the organic layerswere combined, dried over MgSO₄ and evaporated to yield Cap-172 (60 mg,74%) as a red solid which was used without further purification. ¹H NMR(300 MHz, DMSO-d₆) δ ppm 13.03-13.42 (1 H, m), 3.16 (2 H, q, J=7.4 Hz),1.23 (3 H, t, J=7.5 Hz). R_(t)=1.78 min (Cond.-MD1); LC-MS: Anal. Calcd.for [M+H]⁺ C₆H₇ClNO₂S: 191.99; found: 191.99.

Cap-173

Cap-173, Step a

The following diazotization step was adapted from Barton, A. et al.,J.C.S. Perkin Trans I, 159 -164 (1982): A solution of NaNO₂ (150 mg,2.17 mmol) in water (1.0 mL) was added dropwise to a stirred, cold (0°C.) solution of methyl 2-amino-5-ethyl-1,3-thiazole-4-carboxylate (186mg, 1.0 mmol) in 50% H₃PO₂ (3.2 mL). The mixture was stirred at 0° C.for 1 h and allowed to warm up to room temperature where it stirredfurther for 2 h. After recooling to 0° C., the mixture was treatedslowly with a solution of NaOH (85 mg) in water (10 mL). The mixture wasthen diluted with saturated NaHCO₃ solution and extracted twice withether. The organic layers were combined, dried over MgSO₄ andconcentrated to give methyl 5-ethylthiazole-4-carboxylate (i.e.,Cap-173, Step a) (134 mg, 78%) as an orange oil (85% pure) which wasused directly in the next reaction. R_(t)=1.58 min (Cond.-MD1); LC-MS:Anal. Calcd. for [M+H]⁺ C₇H₁₀NO₂S: 172.05; found: 172.05.

Cap-173

To a solution of methyl 5-ethylthiazole-4-carboxylate (134 mg) inTHF/H₂O/MeOH (18 mL/2.7 mL/11 mL) was added LiOH (281 mg, 11.74 mmol).The mixture was stirred at room temperature overnight before it wasconcentrated down and neutralized with 1N HCl in ether (25 mL). Theresidue was extracted twice with ethyl acetate and the organic layerswere combined, dried over MgSO₄ and evaporated to yield Cap-173 (90 mg,73%) as an orange solid which was used without further purification. ¹HNMR (300 MHz, DMSO-d₆) δ ppm 12.74-13.04 (1 H, m), 3.20 (2 H, q, J=7.3Hz), 1.25 (3 H, t, J=7.5 Hz). R_(t)=1.27 min (Cond.-MD1); LC-MS: Anal.Calcd. for [M+H]⁺ C₆H₈NO₂S: 158.03; found: 158.04.

Cap-174

Cap-174, Step a

Triflic anhydride (5.0 g, 18.0 mmol) was added dropwise to a cold (0°C.) solution of methyl 3-hydroxypicolinate (2.5 g, 16.3 mmol) and TEA(2.5 mL, 18.0 mmol) in CH₂Cl₂ (80 mL). The mixture was stirred at 0° C.for 1 h before it was allowed to warm up to room temperature where itstirred for an additional 1 h. The mixture was then quenched withsaturated NaHCO₃ solution (40 mL) and the organic layer was separated,washed with brine, dried over MgSO₄ and concentrated to give methyl3-(trifluoromethylsulfonyloxy)picolinate (i.e., Cap-174, Step a) (3.38g, 73%) as a dark brown oil (>95% pure) which was used directly withoutfurther purification. ¹H NMR (300 MHz, CDCl₃) δ ppm 8.72-8.79 (1 H, m),7.71 (1 H, d, J=1.5 Hz), 7.58-7.65 (1 H, m), 4.04 (3 H, s). R_(t)=1.93min (Cond.-MD1); LC-MS: Anal. Calcd. for [M+H]⁺ C₈H₇F₃NO₅S: 286.00;found: 286.08.

Cap-174

To a solution of methyl 3-(trifluoromethylsulfonyloxy)picolinate (570mg, 2.0 mmol) in DMF (20 mL) was added LiCl (254 mg, 6.0 mmol),tributyl(vinyl)stannane (761 mg, 2.4 mmol) andbis(triphenylphosphine)palladium dichloride (42 mg, 0.06 mmol). Themixture was heated at 100° C. overnight before a saturated solution ofKF (20 mL) was added to the reaction mixture at room temperature. Thismixture was stirred for 4 h before it was filtered through CELITE® andthe pad of CELITE® was washed with ethyl acetate. The aqueous phase ofthe filtrate was then separated and concentrated down in vacuo. Theresidue was treated with 4N HCl in dioxanes (5 mL) and the resultingmixture was extracted with methanol, filtered and evaporated to affordCap-174 (260 mg) as a green solid which was slightly contaminated withinorganic salts but was used without further purification. ¹H NMR (300MHz, DMSO-d₆) δ ppm 8.21 (1 H, d, J=3.7 Hz), 7.81-7.90 (1 H, m), 7.09 (1H, dd, J=7.7, 4.8 Hz), 6.98 (1 H, dd, J=17.9, 11.3 Hz), 5.74 (1 H, dd,J=17.9, 1.5 Hz), 5.20 (1 H, d, J=11.0 Hz). R_(t)=0.39 min (Cond.-MD1);LC-MS: Anal. Calcd. for [M+H]⁺ C₈H₈NO₂: 150.06; found: 150.07.

Cap-175

Cap-175, Step a

To a solution of methyl 3-(trifluoromethylsulfonyloxy)picolinate (i.e.,Cap-174, Step a) (570 mg, 2.0 mmol), an intermediate in the preparationof Cap-174, in DMF (20 mL) was added LiCl (254 mg, 6.0 mmol),tributyl(vinyl)stannane (761 mg, 2.4 mmol) andbis(triphenylphosphine)palladium dichloride (42 mg, 0.06 mmol). Themixture was heated at 100° C. for 4 h before the solvent was removed invacuo. The residue was taken up in acetonitrile (50 mL) and hexanes (50mL) and the resulting mixture was washed twice with hexanes. Theacetonitrile layer was then separated, filtered through CELITE®, andevaporated. Purification of the residue by flash chromatography on aHorizon instrument (gradient elution with 25% ethyl acetate in hexanesto 65% ethyl acetate in hexanes) afforded methyl 3-vinylpicolinate(i.e., Cap-175, Step a) (130 mg, 40%) as a yellow oil. ¹H NMR (300 MHz,CDCl₃) δ ppm 8.60 (1 H, dd, J=4.6, 1.7 Hz), 7.94 (1 H, d, J=7.7 Hz),7.33-7.51 (2 H, m), 5.72 (1 H, d, J=17.2 Hz), 5.47 (1 H, d, J=11.0 Hz),3.99 (3 H, s). R_(t)=1.29 min (Cond.-MD1); LC-MS: Anal. Calcd. for[M+H]⁺ C₉H₁₀NO₂: 164.07; found: 164.06.

Cap-175, Step b

Palladium on carbon (10%, 25 mg) was added to a solution of methyl3-vinylpicolinate (120 mg, 0.74 mmol) in ethanol (10 mL). The suspensionwas stirred at room temperature under an atmosphere of hydrogen for 1 hbefore it was filtered through CELITE® and the pad of CELITE® was washedwith methanol. The filtrate was concentrated down to dryness to yieldmethyl 3-ethylpicolinate (i.e., Cap-175, Step b) which was takendirectly into the next reaction. R_(t)=1.15 min (Cond.-MD1); LC-MS:Anal. Calcd. for [M+H]⁺ C₉H₁₂NO₂: 166.09; found: 166.09.

Cap-175

To a solution of methyl 3-ethylpicolinate in THF/H₂O/MeOH (5 mL/0.75mL/3 mL) was added LiOH (35 mg, 1.47 mmol). The mixture was stirred atroom temperature for 2 d before additional LiOH (80 mg) was added. Afteran additional 24 h at room temperature, the mixture was filtered and thesolvent was removed in vacuo. The residue was then treated with 4N HClin dioxanes (5 mL) and the resulting suspension was concentrated down todryness to yield Cap-175 as a yellow solid which was used withoutfurther purification. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 8.47 (1 H, dd,J=4.8, 1.5 Hz), 7.82-7.89 (1 H, m), 7.53 (1 H, dd, J=7.7, 4.8 Hz), 2.82(2 H, q, J=7.3 Hz), 1.17 (3 H, t, J=7.5 Hz). R_(t)=0.36 min (Cond.-MD1);LC-MS: Anal. Calcd. for [M+H]⁺ C₈H₁₀NO₂: 152.07; found: 152.10.

Cap-176

(S)-2-(4,4-Difluorocyclohexyl)-2-(methoxycarbonylamino)acetic acidCap-176, Step a

A solution of 1,4-dioxaspiro[4.5]decan-8-one (15 g, 96 mmol) in EtOAc(150 mL) was added to a solution of methyl2-(benzyloxycarbonylamino)-2-(dimethoxyphosphoryl)acetate (21.21 g, 64.0mmol) in 1,1,3,3-tetramethylguanidine (10.45 mL, 83 mmol) and EtOAc (150mL). The resulting solution was the stirred at ambient temperature for72 h and then it was diluted with EtOAc (25 mL). The organic layer waswashed with 1N HCl (75 mL), H₂O (100 mL) and brine (100 mL), dried(MgSO₄), filtered and concentrated. The residue was purified viaBIOTAGE® (5% to 25% EtOAc/Hexanes; 300 g column). The combined fractionscontaining the product were then concentrated under vacuum and theresidue was re-crystallized from hexanes/EtOAc to give white crystalsthat corresponded to methyl2-(benzyloxycarbonylamino)-2-(1,4-dioxaspiro[4.5]decan-8-ylidene)acetate(6.2 g) ¹H NMR (400 MHz, CDCl₃-d) δ ppm 7.30-7.44 (5 H, m), 6.02 (1 H,br. s.), 5.15 (2 H, s), 3.97 (4 H, s), 3.76 (3 H, br. s.), 2.84-2.92 (2H, m), 2.47 (2H, t, J=6.40 Hz), 1.74-1.83 (4 H, m). LC (Cond. OL1):R_(t)=2.89 min. LC-MS: Anal. Calcd. for [M+Na]⁺ C₁₉H₂₃NNaO₆: 745.21;found: 745.47.

Cap-176, Step b

Ester Cap-176, Step b was prepared from alkene Cap-176, Step a accordingto the method of Burk, M. J. et al. (J. Am. Chem. Soc., 117:9375-9376(1995)) and references therein): A 500 mL high-pressure bottle wascharged with alkene Cap-176, Step a (3.5 g, 9.68 mmol) in degassed MeOH(200 mL) under a blanket of N₂. The solution was then charged with(−)-1,2-Bis((2S,5S)-2,5-dimethylphospholano)ethane(cyclooctadiene)rhodium(I)tetrafluoroborate(0.108 g, 0.194 mmol) and the resulting mixture was flushed with N₂ (3×)and charged with H₂ (3×). The solution was shaken vigorously under 70psi of H₂ at ambient temperature for 72 h. The solvent was removed underreduced pressure and the remaining residue was taken up in EtOAc. Thebrownish solution was then filtered through a plug of Silica Gel andeluted with EtOAc. The solvent was concentrated under vacuum to afford aclear oil corresponding to ester Cap-176, Step b (3.4 g). ¹H NMR (500MHz, CDCl₃-d) δ ppm 7.28-7.43 (5 H, m), 5.32 (1 H, d, J=9.16 Hz),5.06-5.16 (2 H, m), 4.37 (1 H, dd, J=9.00, 5.04 Hz), 3.92 (4 H, t,J=3.05 Hz), 3.75 (3 H, s), 1.64-1.92 (4 H, m), 1.37-1.60 (5 H, m). LC(Cond. OL1): R_(t)=1.95 min. LC-MS: Anal. Calcd. for [M+H]⁺ C₁₉H₂₆NO₆:364.18; found: 364.27.

Cap-176, Step c

Ester Cap-176, Step b (4.78 g, 13.15 mmol) was dissolved in THF (15 mL)followed by sequential addition of water (10 mL), glacial acetic acid(26.4 mL, 460 mmol) and dichloroacetic acid (5.44 mL, 65.8 mmol). Theresulting mixture was stirred for 72 h at ambient temperature, and thereaction was quenched by slow addition of solid Na₂CO₃ with vigorousstirring until the release of gas was no longer visible. Crude productwas extracted into 10% ethyl acetate-dichloromethane and the organiclayers were combined, dried (MgSO₄) filtered and concentrated. Theresulting residue was purified via BIOTAGE® (0 to 30% EtOAc/Hex; 25 gcolumn) to afford ketone Cap-176, Step c (3.86 g) as a clear oil. ¹H NMR(400 MHz, CDCl₃-d) δ ppm 7.28-7.41 (5 H, m), 5.55 (1 H, d, J=8.28 Hz),5.09 (2 H, s), 4.46 (1 H, dd, J=8.16, 5.14 Hz), 3.74 (3 H, s), 2.18-2.46(5 H, m), 1.96-2.06 (1 H, m), 1.90 (1 H, ddd, J=12.99, 5.96, 2.89 Hz),1.44-1.68 (2 H, m, J=12.36, 12.36, 12.36, 12.36, 4.77 Hz). LC (Cond.OL1): R_(t)=1.66 min. LC-MS: Anal. Calcd. for [M+Na]⁺ C₁₂H₂₁NNaO₅:342.13; found: 342.10.

Cap-176, Step d

DEOXO-FLUOR® (3.13 mL, 16.97 mmol) was added to a solution of ketoneCap-176, Step c (2.71 g, 8.49 mmol) in CH₂Cl₂ (50 mL) followed byaddition of a catalytic amount of EtOH (0.149 mL, 2.55 mmol). Theresulting yellowish solution was stirred at rt overnight. The reactionwas quenched by addition of sat. aq. NaHCO₃ (25 mL) and the mixture wasextracted with EtOAc (3×75 mL)). The combined organic layers were dried(MgSO₄), filtered and dried to give a yellowish oil. The residue waspurified via BIOTAGE® chromatography (2% to 15% EtOAc/Hex; 90 g column)and a white solid corresponding to the difluoro amino acid difluorideCap-176, Step d (1.5 g) was recovered. ¹H NMR (400 MHz, CDCl₃-d) δ ppm7.29-7.46 (5 H, m), 5.34 (1 H, d, J=8.28 Hz), 5.12 (2 H, s), 4.41 (1 H,dd, J=8.66, 4.89 Hz), 3.77 (3 H, s), 2.06-2.20 (2 H, m), 1.83-1.98 (1 H,m), 1.60-1.81 (4 H, m), 1.38-1.55 (2 H, m). ¹⁹F NMR (376 MHz, CDCl₃-d) δppm −92.15 (1 F, d, J=237.55 Hz), −102.44 (1 F, d, J=235.82 Hz). LC(Cond. OL1): R_(t)=1.66 min. LC-MS: Anal. Calcd. for [2M+Na]⁺C₃₄H₄₂F₄N₂NaO₈: 705.28; found: 705.18.

Cap-176, Step e

Difluoride Cap-176, Step d (4 g, 11.72 mmol) was dissolved in MeOH (120mL) and charged with Pd/C (1.247 g, 1.172 mmol). The suspension wasflushed with N₂ (3×) and the reaction mixture was placed under 1 atm ofH₂ (balloon). The mixture was stirred at ambient temperature for 48 h.The suspension was then filtered though a plug of CELITE® andconcentrated under vacuum to give an oil that corresponded to amino acidCap-176, Step e (2.04 g) and that was used without further purification.¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.62 (3 H, s), 3.20 (1 H, d, J=5.77 Hz),1.91-2.09 (2 H, m), 1.50-1.88 (7 H, m), 1.20-1.45 (2 H, m). ¹⁹F NMR (376MHz, DMSO-d₆) δ ppm −89.39 (1 F, d, J=232.35 Hz), −100.07 (1 F, d,J=232.35 Hz). ¹³C NMR (101 MHz, DMSO-d₆) δ ppm 175.51 (1 C, s), 124.10(1 C, t, J=241.21, 238.90 Hz), 57.74 (1 C, s), 51.39 (1 C, s), 39.23 (1C, br. s.), 32.02-33.83 (2 C, m), 25.36 (1 C, d, J=10.02 Hz), 23.74 (1C, d, J=9.25 Hz). LC (Cond. OL2): R_(t)=0.95 min. LC-MS: Anal. Calcd.for [2M+H]⁺ C₁₈H₃₁F₄N₂O₂: 415.22; found: 415.40.

Cap-176, Step f

Methyl chloroformate (1.495 mL, 19.30 mmol) was added to a solution ofamino acid Cap-176, Step e (2 g, 9.65 mmol) and DIEA (6.74 mL, 38.6mmol) in CH₂Cl₂ (100 mL). The resulting solution was stirred at rt for 3h and volatiles were removed under reduced pressure. The residue waspurified via BIOTAGE® (0% to 20% EtOAc/Hex; 90 g column). A clear oilthat solidified upon standing under vacuum and corresponding tocarbamate Cap-176, Step f (2.22 g) was recovered. ¹H NMR (500 MHz,CDCl₃-d) δ ppm 5.27 (1 H, d, J=8.55 Hz), 4.39 (1 H, dd, J=8.85, 4.88Hz), 3.77 (3 H, s), 3.70 (3 H, s), 2.07-2.20 (2 H, m), 1.84-1.96 (1 H,m), 1.64-1.82 (4 H, m), 1.39-1.51 (2 H, m). ¹⁹F NMR (471 MHz, CDCl₃-d) δppm −92.55 (1 F, d, J=237.13 Hz), −102.93 (1 F, d, J=237.12 Hz). ¹³C NMR(126 MHz, CDCl₃-d) δ ppm 171.97 (1 C, s), 156.69 (1 C, s), 119.77-125.59(1 C, m), 57.24 (1 C, br. s.), 52.48 (1 C, br. s.), 52.43 (1 C, s),39.15 (1 C, s), 32.50-33.48 (2 C, m), 25.30 (1 C, d, J=9.60 Hz), 24.03(1 C, d, J=9.60 Hz). LC (Cond. OL1): R_(t)=1.49 min. LC-MS: Anal. Calcd.for [M+Na]⁺ C₁₁H₁₂F₂NNaO₄: 288.10; found: 288.03.

Cap-176

(S)-2-(4,4-Difluorocyclohexyl)-2-(methoxycarbonylamino)acetic acid

A solution of LiOH (0.379 g, 15.83 mmol) in water (25 mL) was added to asolution of carbamate Cap-176, Step f (2.1 g, 7.92 mmol) in THF (75 mL)and the resulting mixture was stirred at ambient temperature for 4 h.THF was removed under vacuum and the remaining aqueous phase wasacidified with 1N HCl solution (2 mL) and then extracted with EtOAc(2×50 mL). The combined organic layers were dried (MgSO₄), filtered andconcentrated to give a white foam corresponding to Cap-176 (1.92 g). ¹HNMR (400 MHz, DMSO-d₆) δ ppm 12.73 (1 H, s), 7.50 (1 H, d, J=8.78 Hz),3.97 (1 H, dd, J=8.53, 6.02 Hz), 3.54 (3 H, s), 1.92-2.08 (2 H, m),1.57-1.90 (5 H, m), 1.34-1.48 (1 H, m), 1.27 (1 H, qd, J=12.72, 3.26Hz). ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm −89.62 (1 F, d, J=232.35 Hz),−99.93 (1 F, d, J=232.35 Hz). LC (Cond. OL2): R_(t)=0.76 min. LC-MS:Anal. Calcd. for [M−H]⁺ C₁₀H₁₄F₂NO₄: 250.09; found: 250.10.

Cap-177a-d

Cap-177a-d, Step a

1,1,3,3-Tetramethylguanidine (0.985 mL, 7.85 mmol) was added to astirred solution of methyl2-(benzyloxycarbonylamino)-2-(dimethoxyphosphoryl)acetate (2.0 g, 6.0mmol) in EtOAc (40 mL) and the mixture was stirred at rt under N₂ for 10min. Then dihydro-2H-pyran-3(4H)-one [23462-75-1] (0.604 g, 6.04 mmol)was added and the mixture was stirred at rt for 16 h. The reactionmixture was then cooled in freezer for 10 min and neutralized with aq.citric acid (1.5 g in 20 mL water). The two phases were partitioned andthe organic layer was washed with 0.25 N aq.HCl and brine, and thendried (MgSO₄) and concentrated to a colorless oil. The crude materialwas purified by flash silica chromatography (loading solvent: DCM,eluted with EtOAc/Hexanes, gradient from 20% to 30% EtOAc) to yield twoisomeric products: The first eluted product was (Z)-methyl2-(benzyloxycarbonylamino)-2-(2H-pyran-3(4H,5H,6H)-ylidene)acetate (490mg) (white solid), and the second was (E)-methyl2-(benzyloxycarbonylamino)-2-(2H-pyran-3(4H,5H,6H)-ylidene)acetate (433mg) (white solid). LC-MS retention time 1.398 min (for Z-isomer) and1.378 min (for E-isomer); m/z 304.08 (for Z-isomer) and 304.16 (forE-isomer) (MH—). LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped with a PHENOMENEX® Luna 10u C18 3.0×50 mm columnusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 4 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 3 min, a hold time of 1 min, and an analysis time of 4 min whereSolvent A was 5% MeOH/95% H₂O/10 mM ammonium acetate and Solvent B was5% H₂O/95% MeOH/10 mM ammonium acetate. MS data was determined using aMICROMASS® Platform for LC in electrospray mode. ¹H NMR (400 MHz,chloroform-d) (for Z-isomer) δ ppm 7.30-7.44 (m, 5 H), 6.18 (br. s., 1H), 5.10-5.17 (m, 2 H), 4.22 (s, 2 H), 3.78 (br. s., 3 H), 2.93-3.02 (m,2 H), 1.80 (dt, J=11.7, 5.8 Hz, 2 H), 1.62 (s, 2 H). ¹H NMR (400 MHz,chloroform-d) (for E-isomer) δ ppm 7.31-7.44 (m, 5 H), 6.12 (br. s., 1H), 5.13-5.17 (m, 2 H), 4.64 (br. s., 2 H), 3.70-3.82 (m, 5 H), 2.49 (t,J=6.5 Hz, 2 H), 1.80 (br. s., 2 H). (Note: the absolute regiochemistrywas determined by ¹H NMR shifts and coupling constants).

Cap-177a-d, Step b

(−)-1,2-Bis((2S,5S)-2,5-dimethylphospholano)ethane(cyclooctadiene)-rhodium(I)tetrafluoroborate(28.2 mg, 0.051 mmol) was added to a stirred solution of (Z)-methyl2-(benzyloxycarbonylamino)-2-(2H-pyran-3 (4H,5H,6H)-ylidene)acetate (310mg, 1.015 mmol) in MeOH (10 mL) and the mixture was vacuum flushed withN₂, followed by H₂, and then the reaction was stirred under H₂ (60 psi)at rt for 2d. The reaction mixture was concentrated and the residue waspurified by flash silica chromatography (loading solvent: DCM, elutedwith 20% EtOAc in hexanes) to yield (S)-methyl2-(benzyloxycarbonylamino)-2-((S)-tetrahydro-2H-pyran-3-yl)acetate (204mg) as clear colorless oil. LC-MS retention time 1.437 min; m/z 307.89(MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatographequipped with a PHENOMENEX® Luna 10u C18 3.0×50 mm column using aSPD-10AV UV-Vis detector at a detector wave length of 220 nM. Theelution conditions employed a flow rate of 4 mL/min, a gradient of 100%Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient timeof 3 min, a hold time of 1 min, and an analysis time of 4 min whereSolvent A was 5% MeOH/95% H₂O/10 mM ammonium acetate and Solvent B was5% H₂O/95% MeOH/10 mM ammonium acetate. MS data was determined using aMICROMASS® Platform for LC in electrospray mode. ¹H NMR (400 MHz,chloroform-d) δ ppm 7.30-7.46 (m, 5 H), 5.32 (d, J=8.8 Hz, 1 H), 5.12(s, 2 H), 4.36 (dd, J=8.9, 5.6 Hz, 1 H), 3.84-3.98 (m, 2 H), 3.77 (s, 3H), 3.28-3.37 (m, 1 H), 3.23 (dd, J=11.3, 10.5 Hz, 1 H), 2.04-2.16 (m, 1H), 1.61-1.75 (m, 3 H), 1.31-1.43 (m, 1 H).

The other stereoisomer ((E)-methyl2-(benzyloxycarbonylamino)-2-(2H-pyran-3(4H,5H,6H)-ylidene)acetate) (360mg, 1.18 mmol) was reduced in a similar manner to yield (S)-methyl2-(benzyloxycarbonylamino)-2-((R)-tetrahydro-2H-pyran-3-yl)acetate (214mg) as clear colorless oil. LC-MS retention time 1.437 min; m/z 308.03(MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatographequipped with a PHENOMENEX® Luna 10u C18 3.0×50 mm column using aSPD-10AV UV-Vis detector at a detector wave length of 220 nM. Theelution conditions employed a flow rate of 4 mL/min, a gradient of 100%Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient timeof 3 min, a hold time of 1 min, and an analysis time of 4 min whereSolvent A was 5% MeOH/95% H₂O/10 mM ammonium acetate and Solvent B was5% H₂O/95% MeOH/10 mM ammonium acetate. MS data was determined using aMICROMASS® Platform for LC in electrospray mode. ¹H NMR (400 MHz,chloroform-d) δ ppm 7.30-7.44 (m, 5 H), 5.31 (d, J=9.0 Hz, 1 H), 5.12(s, 2 H), 4.31 (dd, J=8.7, 6.9 Hz, 1 H), 3.80-3.90 (m, 2 H), 3.77 (s, 3H), 3.37 (td, J=10.8, 3.5 Hz, 1 H), 3.28 (dd, J=11.3, 9.8 Hz, 1 H),1.97-2.10 (m, 1 H), 1.81 (d, J=11.5 Hz, 1 H), 1.61-1.72 (m, 2 H),1.33-1.46 (m, 1 H).

The individual enantiomers of Cap-177a, Step b (Cap-177c, Step b) andCap-177b, Step b (Cap-177d, Step b) were prepared in the same manner andin similar yields utilizing(−)-1,2-Bis((2R,5R)-2,5-dimethylphospholano)ethane(cyclooctadiene)-rhodium(I)tetrafluoroborate as the hydrogenationcatalyst for the olefin reductions of the individual stereoisomerstarting materials.

Cap-177a and Cap-177b, Step c

10% Pd/C (69.3 mg, 0.065 mmol) was added to a solution of (S)-methyl2-(benzyloxycarbonylamino)-2-((S)-tetrahydro-2H-pyran-3-yl)acetate (200mg, 0.651 mmol) and dimethyl dicarbonate [4525-33-1] (0.104 mL, 0.976mmol) in MeOH (10 mL). The reaction mixture was vacuum flushed with N₂,followed by H₂, and then the reaction was stirred under H₂ (55 psi) atrt for 5 h. The reaction mixture was filtered through CELITE®/silica padand the filtrate was concentrated to a colorless oil. The crude oil waspurified by flash silica chromatography (loading solvent: DCM, elutedwith 30% EtOAc in hexanes) to yield product (S)-methyl2-(methoxycarbonylamino)-2-((S)-tetrahydro-2H-pyran-3-yl)acetate (132mg) as colorless oil. LC-MS retention time 0.92 min; m/z 231.97 (MH+).LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equippedwith a PHENOMENEX® Luna 10u C18 3.0×50 mm column using a SPD-10AV UV-Visdetector at a detector wave length of 220 nM. The elution conditionsemployed a flow rate of 4 mL/min, a gradient of 100% Solvent A/0%Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 3 min, ahold time of 1 min, and an analysis time of 4 min where Solvent A was 5%MeOH/95% H₂O/10 mM ammonium acetate and Solvent B was 5% H₂O/95% MeOH/10mM ammonium acetate. MS data was determined using a MICROMASS® Platformfor LC in electrospray mode. ¹H NMR (400 MHz, chloroform-d) δ ppm 5.24(d, J=8.5 Hz, 1 H), 4.34 (dd, J=8.9, 5.6 Hz, 1 H), 3.84-3.97 (m, 2 H),3.77 (s, 3 H), 3.70 (s, 3 H), 3.29-3.38 (m, 1 H), 3.23 (dd, J=11.2, 10.4Hz, 1 H), 2.03-2.14 (m, 1 H), 1.56-1.75 (m, 3 H), 1.32-1.43 (m, 1 H).

Another diastereomer ((S)-methyl2-(benzyloxycarbonylamino)-2-((R)-tetrahydro-2H-pyran-3-yl)acetate) wastransformed in a similar manner to yield (S)-methyl2-(methoxycarbonylamino)-2-((R)-tetrahydro-2H-pyran-3-yl)acetate asclear colorless oil. LC-MS retention time 0.99 min; m/z 231.90 (MH+). LCdata was recorded on a Shimadzu LC-10AS liquid chromatograph equippedwith a PHENOMENEX® Luna 10u C18 3.0×50 mm column using a SPD-10AV UV-Visdetector at a detector wave length of 220 nM. The elution conditionsemployed a flow rate of 4 mL/min, a gradient of 100% Solvent A/0%Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 3 min, ahold time of 1 min, and an analysis time of 4 min where Solvent A was 5%MeOH/95% H₂O/10 mM ammonium acetate and Solvent B was 5% H₂O/95% MeOH/10mM ammonium acetate. MS data was determined using a MICROMASS® Platformfor LC in electrospray mode. ¹H NMR (400 MHz, chloroform-d) δ ppm 5.25(d, J=8.0 Hz, 1 H), 4.29 (dd, J=8.4, 7.2 Hz, 1 H), 3.82-3.90 (m, 2 H),3.77 (s, 3 H), 3.70 (s, 3 H), 3.37 (td, J=10.8, 3.3 Hz, 1 H), 3.28 (t,J=10.5 Hz, 1 H), 1.96-2.08 (m, 1 H), 1.81 (dd, J=12.9, 1.6 Hz, 1 H),1.56-1.72 (m, 2 H), 1.33-1.46 (m, 1 H).

The individual enantiomers of Cap-177a, Step c (Cap-177c, Step c) andCap-177b, Step c (Cap-177d, Step c) were prepared in a similar mannerand is similar yields using the appropriate starting materials fromCap-177a-d, Step b.

Cap-177a and Cap-177b, Step d

To a solution of (S)-methyl2-(methoxycarbonylamino)-2-((S)-tetrahydro-2H-pyran-3-yl)acetate (126mg, 0.545 mmol) in THF (4 mL) stirring at rt was added a solution of 1MLiOH (1.090 mL, 1.090 mmol) in water. The reaction was stirred at rt for3 h, neutralized with 1M HCl (1.1 mL) and extracted with EtOAc (3×10mL). The organics were dried, filtered and concentrated to yield(S)-2-(methoxycarbonylamino)-2-((S)-tetrahydro-2H-pyran-3-yl)acetic acid(Cap-177a) (125 mg) as a clear colorless oil. LC-MS retention time 0.44min; m/z 218.00 (MH+). LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped with a PHENOMENEX® Luna 10u C18 3.0×50 mm columnusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 4 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 3 min, a hold time of 1 min, and an analysis time of 4 min whereSolvent A was 5% MeOH/95% H₂O/10 mM ammonium acetate and Solvent B was5% H₂O/95% MeOH/10 mM ammonium acetate. MS data was determined using aMICROMASS® Platform for LC in electrospray mode. ¹H NMR (400 MHz,chloroform-d) δ ppm 5.28 (d, J=8.8 Hz, 1 H), 4.38 (dd, J=8.7, 5.6 Hz, 1H), 3.96-4.04 (m, 1 H), 3.91 (d, J=11.0 Hz, 1 H), 3.71 (s, 3 H),3.33-3.41 (m, 1 H), 3.24-3.32 (m, 1 H), 2.10-2.24 (m, 1 H), 1.74-1.83(m, 1 H), 1.63-1.71 (m, 2 H), 1.35-1.49 (m, 1 H).

Another diastereomer ((S)-methyl2-(methoxycarbonylamino)-2-((R)-tetrahydro-2H-pyran-3-yl)acetate) wastransformed in a similar manner to yield(S)-2-(methoxycarbonylamino)-2-((R)-tetrahydro-2H-pyran-3-yl)acetic acid(Cap-177b) as clear colorless oil. LC-MS retention time 0.41 min; m/z217.93 (MH+). LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped with a PHENOMENEX® Luna 10u C18 3.0×50 mm columnusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 4 mL/min, a gradient of100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradienttime of 3 min, a hold time of 1 min, and an analysis time of 4 min whereSolvent A was 5% MeOH/95% H₂O/10 mM ammonium acetate and Solvent B was5% H₂O/95% MeOH/10 mM ammonium acetate. MS data was determined using aMICROMASS® Platform for LC in electrospray mode. ¹H NMR (400 MHz,chloroform-d) δ ppm 6.18 (br. s., 1 H), 5.39 (d, J=8.5 Hz, 1 H),4.27-4.37 (m, 1 H), 3.82-3.96 (m, 2 H), 3.72 (s, 3 H), 3.42 (td, J=10.8,3.3 Hz, 1 H), 3.35 (t, J=10.4 Hz, 1 H), 2.01-2.18 (m, 1 H), 1.90 (d,J=11.8 Hz, 1 H), 1.59-1.76 (m, 2 H), 1.40-1.54 (m, 1 H).

The individual enantiomers of Cap-177a (Cap-177c) and Cap-177b(Cap-177d) were prepared in a similar manner and is similar yields usingthe appropriate starting materials from Cap-177a-d, Step c.

Cap-178

Cap-178, Step a

To a solution of (2S,3S,4S)-2-methyl-3,4-dihydro-2H-pyran-3,4-diyldiacetate (5 g, 23.34 mmol) in 20 mL of MeOH in a hydrogenation tank wasadded Pd/C (150 mg, 0.141 mmol). The resulting mixture was hydrogenatedat 40 psi on Parr Shaker for 1 hour. The mixture was then filtered andthe filtrate was concentrated to afford Cap-178, Step a (5.0 g) as aclear oil, which solidified while standing. ¹H NMR (500 MHz, CDCl₃) δppm 4.85-4.94 (1 H, m), 4.69 (1 H, t, J=9.46 Hz), 3.88-3.94 (1 H, m),3.44 (1 H, td, J=12.21, 1.83 Hz), 3.36 (1 H, dq, J=9.42, 6.12 Hz),2.03-2.08 (1 H, m), 2.02 (3 H, s), 2.00 (3 H, s), 1.70-1.80 (1 H, m),1.16 (3 H, d, J=6.10 Hz).

Cap-178, Step b

To a solution of Cap-178, Step a (5.0 g, 23 mmol) in 50 mL of MeOH wasadded several drops of sodium methoxide. After stirring at roomtemperature for 30 min, sodium methoxide (0.1 mL, 23.12 mmol) was addedand the solution was stirred at room temperature overnight. The solventwas then removed under vacuum. The residue was diluted with benzene andconcentrated to afford the corresponding diol as a yellow solid. Thesolid was dissolved in 50 mL of pyridine and to this solution at −35° C.was added benzoyl chloride (2.95 mL, 25.4 mmol) dropwise. The resultingmixture was stirred at −35° C. for 1 hour then at room temperatureovernight. The mixture was diluted with Et₂O and washed with water. Theaqueous layer was extracted with EtOAc (2×). The combined organic layerswere dried with MgSO₄ and concentrated. The crude product was purifiedby flash chromatography (silica gel, 5%-15% EtOAc/Hex) to affordCap-178, Step b (4.5 g) as clear oil which slowly crystallized uponprolonged standing. LC-MS: Anal. Calcd. for [M+Na]⁺ C₁₃H₁₆NaO₄ 259.09;found 259.0; ¹H NMR (500 MHz, CDCl₃) δ ppm 8.02-8.07 (2 H, m), 7.55-7.61(1 H, m), 7.45 (2 H, t, J=7.78 Hz), 5.01 (1 H, ddd, J=11.44, 8.70, 5.49Hz), 3.98 (1 H, ddd, J=11.90, 4.88, 1.53 Hz), 3.54 (1 H, td, J=12.36,2.14 Hz), 3.41 (1 H, t, J=9.00 Hz), 3.31-3.38 (1 H, m), 2.13-2.19 (1 H,m), 1.83-1.94 (1 H, m), 1.36 (3 H, d, J=5.80 Hz).

Cap-178, Step c

To a mixture of NaH (1.143 g, 28.6 mmol) (60% in mineral oil) in 6 mL ofCS₂ was added Cap-178, Step b (4.5 g, 19 mmol) in 40 mL of CS₂ dropwiseover 15 min. The resulting mixture was stirred at room temperature for30 min. The mixture turned light orange with some solid. MeI (14.29 mL,229 mmol) was then added dropwise over 20 min. The mixture was thenstirred at room temperature overnight. The reaction was carefullyquenched with saturated NH₄Cl solution. The mixture was extracted withEtOAc (3×). The combined organic layers were dried with MgSO₄ andconcentrated. The crude product was purified by flash chromatography(silica gel, 6% EtOAc/Hex) to afford Cap-178, Step c (3.13 g) as clearoil. LC-MS: Anal. Calcd. for [M+Na]⁺ C₁₅H₁₈NaO₄S₂ 349.05; found 349.11;¹H NMR (500 MHz, CDCl₃) δ ppm 7.94-8.00 (2 H, m), 7.50-7.58 (1 H, m),7.41 (2 H, t, J=7.78 Hz), 5.96 (1 H, t, J=9.46 Hz), 5.28 (1 H, ddd,J=11.37, 9.38, 5.49 Hz), 4.02 (1 H, ddd, J=11.98, 4.96, 1.68 Hz),3.54-3.68 (2 H, m), 2.48 (3 H, s), 2.31 (1 H, dd), 1.88-1.99 (1 H, m),1.28 (3 H, d).

Cap-178, Step d

To a mixture of Cap-178, Step c (3.13 g, 9.59 mmol) and AIBN (120 mg,0.731 mmol) in 40 mL of benzene at 80° C. was added tri-n-butyltinhydride (10.24 mL, 38.4 mmol). The resulting mixture was stirred atreflux temperature for 20 min then cooled to room temperature. Themixture was diluted with diethyl ether and 100 mL of KF (10 g) aqueoussolution was added and the mixture was stirred vigorously for 30 min.The two layers were then separated and the aqueous phase was extractedwith EtOAc (2×). The organic layer was dried with MgSO₄ andconcentrated. The crude product was purified by flash chromatography(silica gel, deactivated with 3% Et₃N in Hexanes and flushed with 3%Et₃N in Hexanes to remove tributyltin derivative and then eluted with15% EtOAc/Hex) to afford Cap-178, Step d (1.9 g) as clear oil. ¹H NMR(500 MHz, CDCl₃) δ ppm 7.98-8.07 (2 H, m), 7.52-7.58 (1 H, m), 7.43 (2H, t, J=7.63 Hz), 5.08-5.17 (1 H, m), 4.06 (1 H, ddd, J=11.90, 4.88,1.53 Hz), 3.50-3.59 (2 H, m), 2.08-2.14 (1 H, m), 1.99-2.06 (1 H, m),1.69-1.80 (1 H, m), 1.41-1.49 (1 H, m), 1.24 (3 H, d, J=6.10 Hz).

Cap-178, Step e

To a mixture of Cap-178, Step d (1.9 g, 8.63 mmol) in 10 mL of MeOH wasadded sodium methoxide (2 mL, 4.00 mmol) (2 M in methanol). Theresulting mixture was stirred at room temperature for 5 hours. Thesolvent was removed under vacuum. The mixture was neutralized withsaturated NH₄Cl solution and extracted with EtOAc (3×). The organiclayers were dried with MgSO₄ and concentrated to afford Cap-178, Step e(0.8 g) as clear oil. The product was used in the next step withoutfurther purification. ¹H NMR (400 MHz, CDCl₃) δ ppm 4.01 (1 H, ddd,J=11.80, 5.02, 1.76 Hz), 3.73-3.83 (1 H, m), 3.36-3.46 (2 H, m),1.92-2.00 (1 H, m), 1.88 (1 H, m), 1.43-1.56 (1 H, m), 1.23 (3 H, d),1.15-1.29 (1 H, m).

Cap-178, Step f

Tosyl-Cl (2.63 g, 13.77 mmol) was added to a solution of Cap-178, Step e(0.8 g, 6.89 mmol) and pyridine (2.23 mL, 27.5 mmol) in 100 mL ofCH₂Cl₂. The resulting mixture was stirred at room temperature for 3days. 10 mL of water was then added into the reaction mixture and themixture was stirred at room temperature for an hour. The two layers wereseparated and the organic phase was washed with water and 1 N HCl aq.solution. The organic phase was dried with MgSO₄ and concentrated toafford Cap-178, Step f (1.75 g) as a light yellow solid. The product wasused in the next step without further purification. Anal. Calcd. for[M+H]⁺ C₁₃H₁₉O₄S 271.10; found 270.90; ¹H NMR (500 MHz, CDCl₃) δ ppm7.79 (2 H, d, J=8.24 Hz), 7.34 (2 H, d, J=7.93 Hz), 4.53-4.62 (1 H, m),3.94 (1 H, ddd, J=12.13, 4.96, 1.83 Hz), 3.29-3.41 (2 H, m), 2.45 (3 H,s), 1.90-1.97 (1 H, m), 1.79-1.85 (1 H, m), 1.64-1.75 (1 H, m),1.38-1.48 (1 H, m), 1.17 (3 H, d, J=6.10 Hz).

Cap-178, Step g

To a microwave tube was placed ethyl 2-(diphenylmethyleneamino)acetate(1.6 g, 5.92 mmol) and Cap-178, Step f (1.6 g, 5.92 mmol). 10 mL oftoluene was added. The tube was sealed and LiHMDS (7.1 mL, 7.10 mmol) (1N in toluene) was added dropwise under N₂. The resulting dark brownsolution was heated at 100° C. under microwave radiation for 6 hours. Tothe mixture was then added water and the mixture was extracted withEtOAc (3×). The combined organic layers were washed with brine, driedwith MgSO₄ and concentrated to afford a diastereomeric mixture of Cap-3,Step g (3.1 g) as an orange oil. The crude mixture was submitted to thenext step without separation. LC-MS: Anal. Calcd. for [M+H]⁺ C₂₃H₂₈NO₃366.21; found 366.3.

Cap-178, Step h

To a solution of the diastereomeric mixture of ethyl Cap-178, Step g in20 mL of THF was added HCl (30 ml, 60.0 mmol) (2 N aqueous). Theresulting mixture was stirred at room temperature for 1 hour. Themixture was extracted with EtOAc and the aqueous layer was concentratedto afford an HCl salt of Cap-178, Step h (1.9 g) as an orange oil. Thesalt was used in the next step without further purification. LC-MS:Anal. Calcd. for [M+H]⁺ C₁₀H₂₀NO₃ 202.14; found 202.1.

Cap-178, Step i

A solution of 1.9 g Cap-178, Step h (HCl salt), DiPEA (4.19 mL, 24.0mmol) and methyl chloroformate (1.24 mL, 16.0 mmol) in 20 mL of CH₂Cl₂was stirred at room temperature for 1 hour. The mixture was diluted withCH₂Cl₂ and washed with water. The organic layer was dried with Na₂SO₄and concentrated. The crude product was purified by flash chromatography(silica gel, 0-20% EtOAc/Hex) to afford Cap-178, Step i (1.1 g) as ayellow oil. Anal. Calcd. for [M+Na]⁺ C₁₂H₂₁NNaO₅ 282.13; found 282.14;¹H NMR (400 MHz, CDCl₃) δ ppm 5.16 (1 H, br. s.), 4.43-4.58 (1 H, m),4.17-4.28 (2 H, m), 3.89-4.03 (1 H, m), 3.72-3.78 (2 H, m), 3.67-3.72 (3H, m), 2.07-2.19 (1 H, m), 1.35-1.77 (4 H, m), 1.30 (3 H, td, J=7.09,2.89 Hz), 1.19 (3 H, d, J=6.53 Hz).

Cap-178, Step j

To a mixture of Cap-178, Step i (1.1 g, 4.2 mmol) in 5 mL of THF and 2mL of water was added LiOH (6.36 mL, 12.7 mmol) (2 N aq.). The resultingmixture was stirred at room temperature overnight. The mixture was thenneutralized with 1 N HCl aq. and extracted with EtOAc (3×). The combinedorganic layers were dried with MgSO₄ and concentrated to afford Cap-178,Step j (0.8 g) as a clear oil. LC-MS: Anal. Calcd. for [M+H]⁺ C₁₀H₁₈NO₅232.12; found 232.1; ¹H NMR (400 MHz, CDCl₃) δ ppm 5.20 (1 H, d, J=8.28Hz), 4.54 (1 H, t, J=8.16 Hz), 3.95-4.10 (1 H, m), 3.66-3.85 (5 H, m),2.15-2.29 (1 H, m), 1.41-1.85 (4 H, m), 1.23 (3 H, dd, J=6.53, 1.76 Hz).

Cap-178,Step k

To a solution of Cap-178, Step j (240 mg, 1.04 mmol),(S)-1-phenylethanol (0.141 mL, 1.142 mmol) and EDC (219 mg, 1.14 mmol)in 10 mL of CH₂Cl₂ was added DMAP (13.95 mg, 0.114 mmol). The resultingsolution was stirred at room temperature overnight and the solvent wasremoved under vacuum. The residue was taken up into EtOAc, washed withwater, dried with MgSO₄ and concentrated. The crude product was purifiedby chromatography (silica gel, 0-15% EtOAc/Hexanes) to afford Cap-178,Step k as a mixture of two diastereomers. The mixture was separated bychiral HPLC (CHIRALPAK® AS column, 21×250 mm, 10 um) eluting with 90%0.1% diethylamine/Heptane-10% EtOH at 15 mL/min to afford Cap-178, Stepk stereoisomer 1 (eluted first) and Cap-178, Step k stereoisomer 2(eluted second) as white solids. The stereochemistry of the isomers wasnot assigned.

Cap-178, Step k stereoisomer 1 (130 mg): LC-MS: Anal. Calcd. for [M+Na]⁺C₁₈H₂₅NNaO₅ 358.16; found 358.16; ¹H NMR (500 MHz, CDCl₃) δ ppm7.28-7.38 (5 H, m), 5.94 (1 H, q, J=6.71 Hz), 5.12 (1 H, d, J=9.16 Hz),4.55 (1 H, t, J=9.00 Hz), 3.72-3.81 (1 H, m), 3.67 (3 H, s), 3.60-3.70(2 H, m), 1.98-2.08 (1 H, m), 1.59 (3 H, d, J=6.71 Hz), 1.38-1.47 (2 H,m), 1.30 (2 H, t, J=5.34 Hz), 0.93 (3 H, d, J=6.41 Hz).

Cap-178, Stereoisomer 1

To a solution of Cap-178, Step k stereoisomer 1((S)-2-(methoxycarbonylamino)-2-((2S,4R)-2-methyltetrahydro-2H-pyran-4-yl)aceticacid) (150 mg, 0.447 mmol) in 10 mL of EtOH was added Pd/C (20 mg, 0.188mmol) and the mixture was hydrogenated on Parr shaker at 40 psiovernight. The mixture was then filtered and the filtrate wasconcentrated to afford Cap-178, stereoisomer 1 (100 mg) as a stickywhite solid. LC-MS: Anal. Calcd. for [M+H]⁺ C₁₀H₁₈NO₅ 232.12. found232.1; ¹H NMR (500 MHz, CDCl₃) δ ppm 5.14-5.27 (1 H, m), 4.51 (1 H, t,J=8.39 Hz), 3.90-4.07 (1 H, m), 3.60-3.83 (5 H, m), 2.06-2.27 (1 H, m),1.45-1.77 (4 H, m), 1.21 (3 H, d, J=6.41 Hz).

Cap-179 (Enantiomer-1 and Enantiomer-2)

Cap-179, Step a

2,6-Dimethyl-4H-pyran-4-one (10 g, 81 mmol) was dissolved in ethanol(125 mL) and Pd/C (1 g, 0.94 mmol) was added. The mixture washydrogenated in a Parr shaker under H₂ (0.325 g, 161 mmol) (70 psi) atroom temperature for 12 hrs. The catalyst was filtered through a pad ofCELITE® and washed with ethanol. The filtrate was concentrated in vacuumand he residue was purified via BIOTAGE® (2% to 25% EtOAc/Hex; 160 gcolumn). Two fractions of clear oils were isolated. The first elutingone corresponded to (2R,6S)-2,6-dimethyldihydro-2H-pyran-4(3H)-one (1.8g) while the second one corresponded to Cap-179, Step a (1.8 g).(2R,6S)-2,6-Dimethyldihydro-2H-pyran-4(3 H)-one data: ¹H NMR (500 MHz,CDCl₃) δ ppm 3.69 (2 H, ddd, J=11.29, 5.95, 2.29 Hz), 2.24-2.36 (2 H,m), 2.08-2.23 (2 H, m), 1.18-1.34 (6 H, m); ¹³C NMR (126 MHz, CDCl₃) δppm 206.96 (1 C, br. s.), 72.69 (2 C, s), 48.70 (2 C, s), 21.72 (2 C,s).

Cap-179, Step a data: ¹H NMR (500 MHz, CDCl₃) δ ppm 3.69-3.78 (1 H, m),3.36-3.47 (2 H, m), 2.10 (1 H, br. s.), 1.88 (2 H, dd, J=12.05, 4.73Hz), 1.19 (6 H, d, J=6.10 Hz), 1.10 (2 H, q, J=10.70 Hz); ¹³C NMR (126MHz, CDCl₃) δ ppm 71.44 (2 C, s), 67.92 (1 C, s), 42.59 (2 C, s), 21.71(2 C, s).

Cap-179,Step b

DEAD (2.311 mL, 14.59 mmol) was added drop wise to a solution ofCap-179, Step a (0.38 g, 2.92 mmol), 4-nitrobenzoic acid (2.195 g, 13.14mmol) and Ph₃P (3.83 g, 14.59 mmol) in benzene (25 mL). Heat evolutionwas detected and the resulting amber solution was stirred at ambienttemperature for 6 h. Solvent was removed under reduced pressure and theresidue was purified via BIOTAGE® (0 to 15% EtOAc/Hex; 80 g column). Awhite solid corresponding to Cap-179, Step b (0.77 g) was isolated.LC-MS: Anal. Calcd. for [M]⁺ C₁₄H₁₇NO₅: 279.11; found 279.12. ¹H NMR(500 MHz, CDCl₃) δ ppm 8.27-8.32 (2 H, m), 8.20-8.24 (2 H, m), 5.45 (1H, quin, J=2.82 Hz), 3.92 (2 H, dqd, J=11.90, 6.10, 6.10, 6.10, 1.53Hz), 1.91 (2 H, dd, J=14.80, 2.29 Hz), 1.57 (3 H, dt, J=14.65, 3.05 Hz),1.22 (6 H, d, J=6.10 Hz).

Cap-179, Step c

A solution LiOH (0.330 g, 13.8 mmol) in water (8 mL) was added to asolution of Cap-179, Step b (0.77 g, 2.76 mmol) in THF (30 mL) and theresulting mixture was stirred at ambient temperature for 16 h. THF wasremoved under reduced pressure and the aqueous layer was diluted withmore water (20 mL) and extracted with EtOAc (3×15 mL). The combinedorganic layers were dried (MgSO₄), filtered and concentrated undervacuum. An oily residue with a white solid was recovered. The mixturewas triturated with hexanes and the solid was filtered off to yield aclear oil corresponding to Cap-179, Step c (0.34 g). ¹H NMR (500 MHz,CDCl₃) δ ppm 4.21 (1 H, quin, J=2.82 Hz), 3.87-3.95 (2 H, m), 1.72 (1 H,br. s.), 1.63 (2 H, dd, J=14.34, 2.14 Hz), 1.39-1.47 (2 H, m), 1.17 (6H, d, J=6.41 Hz).

Cap-179, Step d

p-Tosyl chloride (3.98 g, 20.89 mmol) was added to a solution ofCap-179, Step c (1.36 g, 10.5 mmol) and Pyridine (3.38 mL, 41.8 mmol) inCH₂Cl₂ (150 mL) at room temperature and stirred for 24 h and thenconcentrated to a yellow oil. The remaining residue was added topyridine (20 mL) and water (30 mL) and the resulting mixture was stirredat ambient temperature for 1½ h. The mixture was extracted with Et₂O (75mL) and the separated organic layer was the washed thoroughly with 1 Naq. HCl (4×50 mL). The organic layer was then dried (MgSO₄), filteredand concentrated. A white solid corresponding to Cap-179, Step d (2.2 g)was isolated. LC-MS: Anal. Calcd. for [2M+H]⁺ C₂₈H₄₁O₈S₂: 569.22; found569.3. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.80 (2 H, d, J=8.28 Hz), 7.35 (2H, d, J=8.03 Hz), 4.89 (1 H, quin, J=2.82 Hz), 3.77-3.88 (2 H, m), 2.46(3 H, s), 1.77 (2 H, dd, J=14.93, 2.89 Hz), 1.36 (2 H, ddd, J=14.31,11.54, 2.76 Hz), 1.13 (6 H, d, J=6.27 Hz).

Cap-179, Step e

LiHMDS (4.30 mL, 4.30 mmol) was added to a solution of Cap-179, Step d(1.02 g, 3.59 mmol) and benzyl 2-(diphenylmethyleneamino)acetate (1.181g, 3.59 mmol) in toluene (25 mL) at room temperature in a sealedmicrowave vial and the resulting mixture was then stirred for 5 h at100° C. under microwave radiation. The reaction was quenched with water(10 mL), extracted with EtOAc, washed with water, dried over MgSO₄,filtrated, and concentrated in vacuum. The residue was purified viaBIOTAGE® (0% to 6% EtOAc/Hex; 80 g column) and a yellow oilcorresponding to Cap-179, Step e (1.2 g) was isolated. Anal. Calcd. for[2M+Na]^(+C) ₅₈H₆₂N₂NaO₆: 905.45; found 905.42. ¹H NMR (400 MHz, CDCl₃)δ ppm 7.64-7.70 (4 H, m), 7.29-7.44 (29 H, m), 7.06 (4 H, dd, J=7.65,1.63 Hz), 5.18 (2 H, d, J=2.01 Hz), 3.89 (2 H, d, J=6.53 Hz), 3.79-3.87(1 H, m), 3.46 (5 H, dquind, J=11.26, 5.87, 5.87, 5.87, 5.87, 1.88 Hz),2.47 (2 H, s), 2.35-2.46 (2 H, m), 1.78 (1 H, dd, J=14.81, 3.01 Hz),1.62-1.65 (1 H, m), 1.61 (2 H, s), 1.36-1.43 (3 H, m), 1.19 (7 H, d,J=6.27 Hz), 1.14 (11 H, dd, J=6.15, 2.89 Hz), 0.86-0.96 (3 H, m).

Cap-179, Step f (Enantiomer-1 and Enantiomer-2)

Cap-179, Step e (2.08 g, 4.71 mmol) was dissolved in THF (100 mL) andtreated with 2 N HCl (9.42 mL, 18.84 mmol). The resulting clear solutionwas stirred at ambient temperature for 4 h and then THF was removedunder reduced pressure. The remaining aqueous layer was extracted withhexanes (3×20 ml) and after diluting with H₂O (20 mL), the aqueous phasewas basified with 1 N NaOH to pH=10 and extracted with EtOAc (3×10 mL).The combined organic layers were dried (MgSO₄), filtered andconcentrated under vacuum. The resulting residue was taken up in CH₂Cl₂(100 mL) and charged with DIEA (2.468 mL, 14.13 mmol) and methylchloroformate (0.401 mL, 5.18 mmol). The resulting solution was stirredat ambient temperature for 2 h. The reaction mixture was quenched withwater (10 mL) and the organic layer was removed under reduced pressure.The aqueous layer was then extracted with EtOAc (3×10 mL) and thecombined organic layers were dried (MgSO₄), filtered and concentrated.The residue was purified via BIOTAGE® (10% EtOAc/Hex; 25 g column). Aclear colorless oil corresponding to Cap-179, Step f (1.05 g) wasrecovered. LC-MS: Anal. Calcd. for [M+H]⁺ C₁₈H₂₆NO₅: 336.18. found336.3. ¹H NMR (500 MHz, CDCl₃) δ ppm 7.32-7.40 (5 H, m), 5.26 (1 H, d,J=8.24 Hz), 5.13-5.24 (2 H, m), 4.36 (1 H, dd, J=8.85, 4.88 Hz), 3.68 (3H, s), 3.32-3.46 (2 H, m), 2.02-2.14 (1 H, m), 1.52 (1 H, d, J=12.82Hz), 1.32 (1 H, d, J=12.51 Hz), 1.11-1.18 (6 H, m), 0.89-1.07 (2 H, m).

A chiral SFC method was developed to separate the racemic mixture byusing 12% methanol as the modifier on a CHIRALPAK® AD-H column (30×250mm, 5 μm) (Temp=35° C., Pressure=150 bar, Wavelength=210 nm, Flowrate=70 mL/min for 8 min, Solvent A=CO₂, Solvent B=MeOH). The twoseparated isomers, Cap-179 Step f (Enantiomer-1) (first eluting) andCap-179 Step f (Enantiomer-2) (second eluting) exhibited the sameanalytical data as the corresponding mixture (see above).

Cap-179, Enantiomer-1 and Enantiomer-2)

Cap-179 Step f (Enantiomer-1) (0.35 g, 1.044 mmol) was dissolved in MeOH(50 mL) in a Parr bottle and charged with Pd/C (0.111 g, 1.044 mmol).The suspension was then placed in a Parr shaker and the mixture wasflushed with N₂ (3×), placed under 40 psi of H₂ (2.104 mg, 1.044 mmol)and shaken at room temperature for 2 h. The catalyst was filtered offthrough a pad of CELITE® and the solvent was removed under reducedpressure, to yield an amber solid corresponding to Cap-179 Enantiomer-1(0.25 g). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.74 (4 H, br. s.), 7.35 (4H, d, J=6.10 Hz), 3.85 (4 H, br. s.), 3.53 (3 H, s), 3.35 (2 H, ddd,J=15.95, 9.99, 6.10 Hz), 1.97 (1 H, br. s.), 1.48 (2 H, t, J=13.28 Hz),1.06 (6 H, d, J=6.10 Hz), 0.82-1.00 (2 H, m).

Cap-179 Enantiomer-2 was prepared similarly: ¹H NMR (500 MHz, DMSO-d₆) δppm 12.50 (1 H, br. s.), 7.31 (1 H, br. s.), 3.84 (1 H, t, J=7.32 Hz),3.53 (3 H, s), 3.29-3.41 (2 H, m), 1.99 (1 H, s), 1.48 (2 H, t, J=14.34Hz), 1.06 (6 H, d, J=6.10 Hz), 0.95 (1 H, q, J=12.21 Hz), 0.87 (1 H, q,J=11.80 Hz). [Note: the minor variation in the ¹H NMR profile of theenantiomers is likely a result of a difference in sample concentration.]

Cap-180 (Racemic Mixture)

Cap-180, Step a

p-Tosyl-Cl (4.39 g, 23.0 mmol) was added to a solution of Cap-179, Stepa (1.50 g, 11.5 mmol) and pyridine (3.73 mL, 46.1 mmol) in CH₂Cl₂ (50mL) at room temperature and stirred for 2 days. The reaction was dilutedwith CH₂Cl₂, washed with water, then 1 N HCl. The organic layer wasdried (MgSO₄) and concentrated to a yellow oil which was purified viaBIOTAGE® (5% to 20% EtOAc/Hex; 40 g column). A clear oil that solidifiedunder vacuum and corresponding to Cap-180, Step a (2.89 g) was isolated.LC-MS: Anal. Calcd. for [2M+Na]⁺ C₂₈H₄₀NaO₈S₂: 591.21; found 591.3. ¹HNMR (500 MHz, CDCl₃) δ ppm 7.80 (2 H, d, J=8.24 Hz), 7.35 (2 H, d,J=7.93 Hz), 4.59 (1 H, tt, J=11.37, 4.96 Hz), 3.36-3.46 (2 H, m), 2.46(3 H, s), 1.91 (2 H, dd, J=12.05, 5.04 Hz), 1.37 (2 H, dt, J=12.67,11.52 Hz), 1.19 (6 H, d, J=6.10 Hz).

Cap-180, Step b

LiHMDS IN (7.09 mL, 7.09 mmol) was added to a solution of Cap-180, Stepa (1.68 g, 5.91 mmol) and ethyl 2-(diphenylmethyleneamino)acetate (1.579g, 5.91 mmol) in toluene (30 mL) at room temperature and the resultingmixture was then stirred for 16 h at 85° C. The reaction was quenchedwith water (50 mL), extracted with EtOAc, washed with water, dried overMgSO₄, filtrated, and concentrated in vacuo. The residue was purifiedvia BIOTAGE® (0% to 15% EtOAc/Hex; 40 g column). A clear yellowish oilcorresponding to Cap-180, Step b (racemic mixture; 0.64 g) was isolated.LC-MS: Anal. Calcd. for [M+H]⁺ C₂₄H₃₀NO₃: 380.22; found 380.03. ¹H NMR(400 MHz, CDCl₃) δ ppm 7.64-7.70 (2 H, m), 7.45-7.51 (3 H, m), 7.38-7.44(1 H, m), 7.31-7.37 (2 H, m), 7.13-7.19 (2 H, m), 4.39 (1 H, d, J=10.54Hz), 4.16-4.26 (2 H, m), 3.29-3.39 (1 H, m), 2.93-3.03 (1 H, m), 2.70 (1H, m, J=9.41, 4.14 Hz), 1.42-1.49 (2 H, m), 1.31-1.37 (1 H, m), 1.29 (4H, t, J=7.15 Hz), 1.04 (6 H, dd, J=7.78, 6.27 Hz).

Cap-180, Step c

Cap-180, Step b (0.36 g, 0.949 mmol) was dissolved in THF (10 mL) andtreated with 2 N HCl (1.897 mL, 3.79 mmol). The resulting clear solutionwas stirred at ambient temperature for 20 h and THF was removed underreduced pressure. The remaining aqueous layer was extracted with hexanes(3×20 mL) and after diluting with H₂O (20 mL), the aqueous phase wasbasified with 1 N NaOH to pH=10 and extracted with EtOAc (3×10 mL). Thecombined organic layers were dried (MgSO₄), filtered and concentratedunder vacuum. The resulting residue was taken up in CH₂Cl₂ (10.00 mL)and charged with DIEA (0.497 mL, 2.85 mmol) and methyl chloroformate(0.081 mL, 1.044 mmol). The resulting solution was stirred at ambienttemperature for 2 h and the reaction mixture was quenched with water (10mL) and the organic layer was removed under reduced pressure. Aqueouslayer was extracted with EtOAc (3×10 mL) and the combined organic layerswere dried (MgSO₄), filtered and concentrated. An amber oilcorresponding to Cap-180, Step c (0.21 g) was recovered and it was usedwithout further purification. LC-MS: Anal. Calcd. for [M+H]⁺ C₁₃H₂₄NO₅:273.17; found 274.06. ¹H NMR (400 MHz, CDCl₃) δ ppm 5.20 (1 H, d, J=8.03Hz), 4.59 (1 H, t, J=10.16 Hz), 4.11-4.27 (3 H, m), 3.69-3.82 (2 H, m),3.64 (3 H, s), 1.95-2.07 (1 H, m), 1.63 (1 H, d, J=13.80 Hz), 1.41 (2 H,dd, J=8.03, 4.02 Hz), 1.31-1.37 (1 H, m), 1.26 (3 H, t, J=7.15 Hz), 1.16(1 H, d, J=6.27 Hz), 1.12 (6 H, dd, J=6.15, 3.89 Hz).

Cap-180 (Racemic Mixture)

Cap-180, Step c (0.32 g, 1.2 mmol) was dissolved in THF (10 mL) andcharged with LiOH (0.056 g, 2.342 mmol) in water (3.33 mL) at 0° C. Theresulting solution was stirred at rt for 2 h. THF was removed underreduced pressure and the remaining residue was diluted with water (15mL) and washed with Et₂O (2×10 mL). The aqueous layer was then acidifiedwith 1N HCl to pH ˜2 and extracted with EtOAc (3×15 mL). The combinedorganic layers were dried (MgSO₄), filtered and concentrated undervacuum to yield Cap-180 (racemic mixture) (0.2 g) as a white foam.LC-MS: Anal. Calcd. for [M+H]⁺ C₁₁H₂₀NO₅: 246.13; found 246.00. ¹H NMR(400 MHz, CDCl₃) δ ppm 5.14 (1 H, d, J=9.03 Hz), 4.65 (1 H, t, J=9.91Hz), 3.63-3.89 (5 H, m), 1.99-2.13 (1 H, m), 1.56-1.73 (2 H, m),1.48-1.55 (1 H, m), 1.35-1.48 (1 H, m), 1.27 (1 H, br. s.), 1.17 (6 H,d, J=6.02 Hz).

Cap-185 (Enantiomer-1 and Enantiomer-2)

Cap-185, Step a

To a mixture of furan (1.075 mL, 14.69 mmol) and zinc (1.585 g, 24.24mmol) in 1 mL of THF was added 1,1,3,3-tetrabromopropan-2-one (8.23 g,22.03 mmol) and triethyl borate (5.25 mL, 30.8 mmol) in 4 mL of THFdropwise during 1 hour in dark. The resulting mixture was stirred atroom temperature in dark for 17 hours. The resulting dark brown mixturewas cooled to −15° C., and 6 mL of water was added. The mixture waswarmed to 0° C. and stirred at this temperature for 30 min. The mixturewas then filtered and washed with ether. The filtrate was diluted withwater and extracted with ether (3×). The combined organic layers weredried with MgSO₄ and concentrated to afford dark brown oil. The darkbrown oil was dissolved in 6 mL of MeOH and the solution was addeddropwise to a mixture of zinc (4.99 g, 76 mmol), copper (I) chloride(0.756 g, 7.64 mmol) and ammonium chloride (5.4 g, 101 mmol) in 20 mL ofMeOH. The reaction temperature was maintained below 15° C. duringaddition. The mixture was then stirred at room temperature for 20 hours,filtered, and the filtrate was diluted with water and extracted withCH₂Cl₂ (3×). The combined organic layers were dried with MgSO₄ andconcentrated. The crude product was purified by flash chromatography(silica gel, 0-14% EtOAc/Hex) to afford Cap-185, Step a as a white solid(1.0 g) as a white solid, which turned yellow soon. ¹H NMR (500 MHz,CDCl₃) δ ppm 6.24 (2 H, s), 5.01 (2 H, d, J=4.88 Hz), 2.73 (2 H, dd,J=16.94, 5.04 Hz), 2.31 (2 H, d, J=16.79 Hz).

Cap-185, Step b

To a solution of Cap-185, Step a (240 mg, 1.933 mmol) in 2 mL of THF at−78° C. was added L-selectride (3.87 mL, 3.87 mmol) (1 M in THF)dropwise over 100 min. The resulting mixture was stirred at −78° C. for1 hour and then at room temperature overnight. The mixture was thencooled to 0° C., 4 mL of 20% NaOH aqueous solution was added, followedby 2 mL of H₂O₂ (30% water solution) dropwise. The resulting mixture wasstirred for 1 hour and then neutralized with 6N HCl (˜5 mL). The aqueouslayer was saturated with NaCl and extracted with CH₂Cl₂ (3×). Thecombined organic layers were dried with MgSO₄ and concentrated. Thecrude product was purified by flash chromatography (silica gel, 0-40%EtOAc/Hex) to afford Cap-185, Step b (180 mg) as clear oil. ¹H NMR (400MHz, CDCl₃) δ ppm 6.49 (2 H, s), 4.76 (2 H, d, J=4.27 Hz), 3.99 (1 H, t,J=5.77 Hz), 2.29 (2 H, ddd, J=15.18, 5.65, 4.02 Hz), 1.70-1.78 (2 H, m).

Cap-185, Step c

p-Tosyl-Cl (544 mg, 2.85 mmol) was added to a solution of Cap-185, Stepb (180 mg, 1.427 mmol) and pyridine (0.462 mL, 5.71 mmol) in 5 mL ofCH₂Cl₂ (5 mL) and the mixture was stirred at room temperature for 2days. The reaction was diluted with CH₂Cl₂ and washed with 1 N aq. HCl.The aqueous layer was extracted with CH₂Cl₂ (2×). The combined organiclayers were dried with MgSO₄ and concentrated. The crude product waspurified by flash chromatography (silica gel, 0-15% EtOAc/Hex) to affordCap-185, Step c (210 mg) as a white solid. ¹H NMR (500 MHz, CDCl₃) δ ppm7.73 (2 H, d, J=8.24 Hz), 7.32 (2 H, d, J=8.24 Hz), 6.25 (2 H, s), 4.76(1 H, t, J=5.65 Hz), 4.64 (2 H, d, J=3.66 Hz), 2.44 (3 H, s), 2.18 (2 H,td, J=10.07, 5.49 Hz), 1.71 (2 H, d, J=15.56 Hz).

Cap-185, Step d

A microwave tube was charged with benzyl2-(diphenylmethyleneamino)acetate (1.5 g, 4.57 mmol) and Cap-185, Step c(1.28 g, 4.57 mmol) in 5 mL of toluene. The tube was sealed and LiHMDS(5.5 mL, 5.5 mmol) (1 N in toluene) was added dropwise under N₂. Theresulting dark brown solution was heated at 100° C. in microwave for 5hours. To the mixture was then added water and EtOAc. The layers wereseparated and the water phase was extracted with EtOAc (2×). Thecombined organic layers were concentrated to afford Cap-185, Step d as aracemic mixture of. The crude mixture was submitted to the next stepwithout purification or separation. LC-MS: Anal. Calcd. for [M+H]⁺C₂₉H₂₈NO₃ 438.21; found 438.4.

Cap-185, Step e

To a solution of the racemic mixture of Cap-185, Step d in 30 mL of THFwas added HCl (20 mL) (2 N aq.). The resulting mixture was stirred atroom temperature for 2 hours. After the reaction was done as judged byTLC, the two layers were separated. The aqueous layer was washed withEtOAc, neutralized with sat. NaHCO₃ aq. solution and then extracted withEtOAc (3×). The combined organic layers were dried with MgSO₄ andconcentrated to afford Cap-185, Step e. LC-MS: Anal. Calcd. for [M+H]⁺C₁₆H₂₀NO₃ 274.14; found 274.12.

Cap-185, Step f

A solution of the crude Cap-185, Step e, DiPEA (1.24 mL, 7.1 mmol) andmethyl chloroformate (0.55 mL, 7.1 mmol) in 5 mL of CH₂Cl₂ was stirredat room temperature for 1 hour. The mixture was then diluted with CH₂Cl₂and washed with water. The organic layer was dried with Na₂SO₄ andconcentrated. The crude product was purified by flash chromatography(silica gel, 0-40% EtOAc/Hex) to afford 700 mg of the racemic mixture.The mixture was then separated by chiral HPLC (CHIRALPAK® AD-H column,30×250 mm, 5 um) eluting with 88% CO₂-12% EtOH at 70 mL/min to afford240 mg of Enantiomer-1 and 310 mg of Enantiomer-2 of Cap-1, Step f aswhite solids. Enantiomer-1: LC-MS: Anal. Calcd. for [M+H]⁺ C₁₈H₂₂NO₅332.15; found 332.3. ¹H NMR (500 MHz, CDCl₃) δ ppm 7.30-7.40 (5 H, m),6.03-6.16 (2 H, m), 5.09-5.26 (3 H, m), 4.65-4.74 (2 H, m), 4.33 (1 H,dd, J=9.16, 4.88 Hz), 3.67 (3 H, s), 2.27-2.38 (1 H, m), 1.61-1.69 (1 H,m), 1.45-1.56 (1 H, m), 1.34 (1 H, dd, J=13.43, 5.19 Hz), 1.07 (1H, dd,J=13.12, 5.19 Hz). Enantiomer-2: LC-MS: Anal. Calcd. for [M+H]⁺C₁₈H₂₂NO₅ 332.15; found 332.06.

Cap-185 (Enantiomer-1 and Enantiomer-2)

To a hydrogenation bottle containing a solution Cap-185, Step f(Enantiomer-2) (300 mg, 0.905 mmol) in 10 mL of MeOH was added Pd/C (15mg, 0.141 mmol) under a cover of nitrogen. The mixture was hydrogenatedon a Parr shaker at 40 psi for 3 hours. The mixture was then filteredand the filtrate was concentrated to afford Cap-185 (Enantiomer-2) (200mg) as a white solid. LC-MS: Anal. Calcd. for [M+H]⁺ C₁₁H₁₈NO₅ 244.12;found 244.2. ¹H NMR (500 MHz, CDCl₃) δ ppm 5.33 (1 H, br. s.), 4.46 (2H, d), 4.28 (1 H, br. s.), 3.68 (3 H, s), 2.35 (1 H, br. s.), 1.91-2.03(2 H, m), 1.56-1.80 (4 H, m), 1.36-1.55 (2 H, m). [Note: Cap-185(Enantiomer-1) can be obtained in a similar fashion.]

Cap-186

To a solution of the ester Cap-185, Step f (Enantiomer-2) (150 mg, 0.453mmol) in 4 mL of MeOH was added NaOH (4 mL of 1 N in water, 4.00 mmol).The resulting mixture was stirred at room temperature for 3 hours. Themethanol was then removed under vacuum, and the residue was neutralizedwith 1 N HCl solution and extracted with EtOAc (3×). The combinedorganic layers were dried with MgSO₄ and concentrated to afford Cap-186that was contaminated with some benzyl alcohol (sticky white solid; 115mg). LC-MS: Anal. Calcd. for [M+H]⁺ C₁₁H₁₆NO₅ 242.10; found 242.1. ¹HNMR (500 MHz, CDCl₃) δ ppm 6.10-6.19 (2 H, m), 5.36 (1 H, d, J=8.85 Hz),4.75-4.84 (2 H, m), 4.28 (1 H, dd, J=8.55, 4.58 Hz), 3.68 (3 H, s),2.33-2.45 (1 H, m), 1.60-1.72 (2 H, m), 1.30-1.48 (2 H, m).

Cap-187

Cap-187, Step a

To a solution of Cap-178, Step e (2.2 g, 18.94 mmol), PPh₃ (24.84 g, 95mmol) and 4-nitrobenzoic acid (14.24 g, 85 mmol) in 30 mL of benzene wasadded DEAD (42.9 mL, 95 mmol) dropwise. The resulting light orangesolution was stirred at room temperature overnight. The solvent was thenremoved under vacuum and the residue was purified by flashchromatography (silica gel, 0-15% EtOAc/Hex) to afford Cap-187, Step a(2.3 g) as a white solid. ¹H NMR (500 MHz, CDCl₃) δ ppm 8.27-8.34 (2 H,m), 8.20-8.26 (2 H, m), 5.45 (1 H, t, J=2.90 Hz), 3.83-3.96 (3 H, m),1.90-2.03 (2 H, m), 1.80-1.88 (1 H, m), 1.61-1.70 (1 H, m), 1.21 (3 H,d, J=6.10 Hz).

Cap-187, Step b

To a solution of Cap-187, Step a (2.3 g, 8.67 mmol) in 10 mL of MeOH wasadded sodium methoxide (2.372 mL, 8.67 mmol) (25% in Methanol). Theresulting mixture was stirred at room temperature for 3 hours. Water wasadded, and the mixture was extracted with EtOAc (5×). The combinedorganic layers were dried with MgSO₄ and concentrated. The crude productwas purified by flash chromatography (silica gel, 0-15% EtOAc/Hex, then15-50% EtOAc/Hex) to afford Cap-187, Step b (0.85 g) as clear oil. ¹HNMR (500 MHz, CDCl₃) δ ppm 4.19-4.23 (1 H, m), 3.82-3.91 (2 H, m),3.73-3.79 (1 H, m), 1.79-1.88 (1 H, m), 1.62-1.68 (1 H, m), 1.46-1.58 (2H, m), 1.14 (3 H, d, J=6.10 Hz).

Cap-187

The individual enantiomers of Cap-187 were synthesized from Cap-187,Step b according to the procedure described for Cap-178. LC-MS: Anal.Calcd. for [M+H]⁺ C₁₀H₁₈NO₅ 232.12; found 232.1. ¹H NMR (400 MHz, CDCl₃)δ ppm 5.26 (1 H, d, J=7.78 Hz), 4.32-4.43 (1 H, m), 4.07 (1 H, dd,J=11.54, 3.51 Hz), 3.72 (3 H, s), 3.39-3.50 (2H, m), 2.08-2.23 (1 H, m),1.54-1.68 (1 H, m), 1.38-1.52 (1 H, m), 1.11-1.32 (5 H, m).

Cap-188 (Four Stereoisomers)

Cap-188, Step a

To a solution of 2,2-dimethyldihydro-2H-pyran-4(3H)-one (2 g, 15.60mmol) in 50 mL of MeOH was slowly added sodium borohydride (0.649 g,17.16 mmol). The resulting mixture was stirred at room temperature for 3hours. To the mixture was then added 1 N HCl aqueous solution until itcrosses into acidic pH range and then extracted with EtOAc (3×). Thecombined organic layers were dried with MgSO₄ and concentrated to affordCap-188, Step a (1.9 g) as clear oil. The product was used in the nextstep without purification. ¹H NMR (400 MHz, CDCl₃) δ ppm 3.91-4.02 (1 H,m), 3.79-3.86 (1 H, m), 3.63 (1 H, td, J=12.05, 2.51 Hz), 1.82-1.93 (2H, m), 1.40-1.53 (1 H, m), 1.29-1.38 (1 H, m), 1.27 (3 H, s), 1.20 (3 H,s).

Cap-188.1 and Cap-188.2, Step b

p-Tosyl-Cl (5.56 g, 29.2 mmol) was added to a solution of Cap-188, Stepa (1.9 g, 14.59 mmol) and pyridine (4.72 mL, 58.4 mmol) in 100 mL ofCH₂Cl₂. The resulting mixture was stirred at room temperature for 3days. To the reaction was added 10 mL of water, and the mixture wasstirred at room temperature for an additional hour. The two layers wereseparated and the organic phase was washed with water and 1 N HClaqueous solution. The organic phase was dried with MgSO₄ andconcentrated to afford the mixture of two enantiomers as a light yellowsolid. The mixture was then separated by chiral HPLC (CHIRALPAK® ADcolumn, 21×250 mm, 10 um) eluting with 92% 0.1% diethylamine/Heptane-8%EtOH at 15 mL/min to afford Cap-188.1, Step b (1.0 g) and Cap-188.2,Step b (1.0 g). The absolute stereochemistry of the two enantiomers wasnot assigned. Cap-188.1, Step b: LC-MS: Anal. Calcd. for [2M+Na]⁺C₂₈H₄₀NaO₈S₂ 591.21; found 591.3. ¹H NMR (500 MHz, CDCl₃) δ ppm 7.79 (2H, d, J=8.24 Hz), 7.34 (2 H, d, J=8.24 Hz), 4.72-4.81 (1 H, m), 3.78 (1H, dt, J=12.44, 4.16 Hz), 3.53-3.61 (1 H, m), 2.45 (3 H, s), 1.75-1.86(2 H, m), 1.61-1.71 (1 H, m), 1.52-1.60 (1 H, m), 1.22 (3 H, s), 1.14 (3H, s). Cap-188.2, Step b: LC-MS: Anal. Calcd. for [2M+Na]⁺ C₂₈H₄₀NaO₈S₂591.21; found 591.3.

Cap-188

The four stereoisomers of Cap-188 could be synthesized from Cap-188.1,Step b and Cap-188.2, Step b, according to the procedure described forthe preparation of Cap-178. Cap-188 (Steroisomer-1): LC-MS: Anal. Calcd.for [M+Na]⁺ C_(1i)H₁₉NNaO₅ 268.12; found 268.23. ¹H NMR (500 MHz, CDCl₃)δ ppm 5.32 (1 H, d, J=8.55 Hz), 4.26-4.35 (1 H, m), 3.57-3.82 (5 H, m),2.11-2.34 (1 H, m), 1.25-1.58 (4 H, m), 1.21 (6 H, d, J=6.10 Hz).Cap-188 (Stereoisomer-2): LC-MS: Anal. Calcd. for [M+H]⁺ C₁₁H₂₀NO₅246.13; found 246.1. ¹H NMR (500 MHz, CDCl₃) δ ppm 5.25 (1 H, d, J=8.55Hz), 4.33 (1 H, dd, J=8.39, 5.04 Hz), 3.80 (1 H, dd, J=11.90, 3.97 Hz),3.62-3.76 (4 H, m), 2.20-2.32 (1 H, m), 1.52-1.63 (1 H, m), 1.27-1.49 (3H, m), 1.22 (6 H, d, J=14.04 Hz).

Cap-189

Cap-189, Step a

To a solution of phenylmagnesium bromide (113 mL, 340 mmol) (3 M inether) in 100 mL of ether was added dropwise exo-2,3-epoxynorbornane (25g, 227 mmol) in 50 mL of ether. After the initial exotherm, the mixturewas heated to reflux overnight. The reaction was then cooled to roomtemperature and quenched carefully with water (˜10 mL). The mixture wasdiluted with ether and washed with a 3 N HCl aqueous solution (˜160 mL).The aqueous layer was extracted with ether (2×) and the combined organiclayers were dried with MgSO₄ and concentrated. The crude product waspurified by flash chromatography (silica gel, 0-18% EtOAc/Hex) to affordCap-189, Step a (11 g). ¹H NMR (400 MHz, CDCl₃) δ ppm 6.03-6.11 (2 H,m), 3.76 (1 H, d, J=11.29 Hz), 2.72-2.81 (2 H, m), 1.98 (1 H, d, J=11.29Hz), 1.67-1.76 (2 H, m), 0.90-0.97 (2 H, m).

Cap-189, Step b

To a solution of oxalyl chloride (59.9 mL, 120 mmol) in 200 mL of CH₂Cl₂at −78° C. was added DMSO (17.01 mL, 240 mmol) in 100 mL of CH₂Cl₂. Themixture was stirred for 10 min, and Cap-189, Step a (11 g, 100 mmol) in150 mL of CH₂Cl₂ was added followed by Et₃N (72.4 mL, 519 mmol) in 30 mLof CH₂Cl₂. The mixture was stirred at −78° C. for 30 min and then warmedto room temperature. Water (150 mL) was added and the mixture wasstirred at room temperature for 30 mins. The two layers were thenseparated, and the aqueous layer was extracted with CH₂Cl₂ (2×). Theorganic layers were combined, dried with MgSO₄ and concentrated. Thecrude product was purified by flash chromatography (silica gel, 0-5%EtOAc/Hex) to afford Cap-189, Step b (5.3 g) as a light yellow oil. ¹HNMR (500 MHz, CDCl₃) δ ppm 6.50-6.55 (2 H, m), 2.78-2.84 (2 H, m),1.92-1.99 (2 H, m), 1.17-1.23 (2 H, m).

Cap-189, Step c

A mixture of Cap-189, Step b (5.3 g, 49.0 mmol), p-toluenesulfonic acidmonohydrate (1.492 g, 7.84 mmol) and ethylene glycol (4.10 mL, 73.5mmol) in 100 mL of benzene was refluxed for 4 hours and then stirred atroom temperature overnight. The reaction was partitioned between Et₂Oand aqueous sat. NaHCO₃ solution and the two layers were separated. Theorganic layer was washed with brine, dried with MgSO₄ and concentrated.The crude product was purified by flash chromatography (silica gel, 0-6%EtOAc/Hex) to afford Cap-189, Step c (5.2 g) as a clear oil. ¹H NMR (400MHz, CDCl₃) δ ppm 6.20 (2 H, t, J=2.13 Hz), 3.90-3.97 (2 H, m),3.81-3.89 (2 H, m), 2.54 (2 H, m), 1.89-1.99 (2 H, m), 0.95-1.03 (2 H,m).

Cap-189, Step d

A solution of Cap-189, Step c (5.2 g, 34.2 mmol) in 60 mL of MeOH and 50mL of CH₂Cl₂ was cooled to −78° C. and treated with ozone gas until alight blue color was apparent. The reaction was then bubbled with N₂ toremove the excess ozone gas (blue color disappeared) and sodiumborohydride (1.939 g, 51.3 mmol) was added into the reaction. Thereaction was then warmed to 0° C. Acetone was added into the mixture toquench the excess sodium borohydride. The mixture was concentrated andthe residue was purified by flash chromatography (silica gel, 100%EtOAc) to afford Cap-189, Step d (5.0 g) as a clear oil. ¹H NMR (400MHz, CDCl₃) δ ppm 3.99-4.09 (4 H, m), 3.68 (4 H, m), 2.17-2.29 (2 H, m),1.92-2.10 (2 H, m), 1.77-1.88 (2 H, m), 1.57-1.70 (2 H, m).

Cap-189, Step e

To a solution of Cap-189, Step d (1 g, 5.31 mmol) in 20 mL of CH₂Cl₂ wasadded silver oxide (3.8 g), p-Ts-Cl (1.215 g, 6.38 mmol) and KI (0.176g, 1.063 mmol). The resulting solution was stirred at room temperaturefor 3 days. The mixture was then filtered and the filtrate wasconcentrated. The crude product was purified by flash chromatography(silica gel, 60% EtOAc/Hex) to afford Cap-189, Step e (0.79 g) as clearoil. LC-MS: Anal. Calcd. for [M+Na]⁺ C₁₆H₂₂NaO₆S 365.10. found 365.22.¹H NMR (400 MHz, CDCl₃) δ ppm 7.80 (2 H, d, J=8.28 Hz), 7.36 (2 H, d,J=8.03 Hz), 4.11-4.17 (1 H, m), 3.85-4.06 (5 H, m), 3.64-3.71 (1 H, m),3.55-3.63 (1 H, m), 2.47 (3 H, s), 2.32-2.43 (1 H, m), 2.15-2.27 (1 H,m), 1.70-1.89 (2 H, m), 1.52-1.66 (1 H, m), 1.35-1.47 (1 H, m).

Cap-189, Step f

To a solution of Cap-189, Step e (2.2 g, 6.43 mmol) in 40 mL of MeOH wasadded potassium carbonate (1.776 g, 12.85 mmol). The resulting mixturewas stirred at room temperature overnight. The mixture was then dilutedwith water and EtOAc. The two layers were separated. The aqueous layerwas extracted with EtOAc (2×). The combined organic layers were washedwith brine, dried with MgSO₄ and concentrated. The crude product waspurified by flash chromatography (silica gel, 0-15% EtOAc/Hex) to affordCap-189, Step f (0.89 g, 5.23 mmol, 81%) as clear oil. ¹H NMR (400 MHz,CDCl₃) δ ppm 3.89-4.02 (6 H, m), 3.58 (2 H, dd, J=10.79, 2.51 Hz),1.69-1.89 (6 H, m).

Cap-189, Step g

To the solution of Cap-189, Step f (890 mg, 5.23 mmol) in 15 mL of THFwas added HCl (15 mL, 45.0 mmol) (3 M aqueous). The resulting mixturewas stirred at room temperature overnight. The mixture was then dilutedwith ether and the two layers were separated. The aqueous phase wasextracted with ether (2×) and the combined organic layers were driedwith MgSO₄ and concentrated to afford Cap-189, Step g (0.95 g,containing some residual solvents). The product was used in the nextstep without purification. ¹H NMR (500 MHz, CDCl₃) δ ppm 3.95-4.00 (2 H,m), 3.85 (2 H, d, J=10.68 Hz), 2.21-2.28 (2 H, m), 1.99-2.04 (2 H, m),1.90-1.96 (2 H, m).

Cap-189, Step h (Enantiomer-1 and Enantiomer-2)

To a solution of (+/−)-benzyloxycarbonyl-α-phosphonoglycine trimethylester (1733 mg, 5.23 mmol) in 6 mL of THF at −20° C. was added1,1,3,3-tetramethylguanidine (0.723 mL, 5.75 mmol). The resultant lightyellow mixture was stirred at −20° C. for 1 hour, and Cap-189, Step g(660 mg, 5.23 mmol) in 3 mL of THF was added and mixture was thenstirred at room temperature for 3 days. The reaction mixture was thendiluted with EtOAc, washed with a 0.1; N HCl aq. solution. The aqueouslayer was extracted with EtOAc (2×) and the combined organic layers weredried with MgSO₄ and concentrated. The crude product was purified byflash chromatography (silica gel, 0-4% EtOAc/CH₂Cl₂) to afford 960 mg ofthe racemic mixture. The mixture was separated by chiral HPLC(CHIRALPAK® AD column, 21×250 mm, 10 um) eluting with 90% 0.1%diethylamine/Heptane-10% EtOH at 15 mL/min to afford Cap-189, Step h(Enantiomer-1; 300 mg) and Cap-189, Step h (Enantiomer-2; 310 mg) aswhite solids. Cap-189, Step h (Enantiomer-1): LC-MS: Anal. Calcd. for[M+H]⁺ C₁₈H₂₂NO₅ 332.15; found 332.2. ¹H NMR (500 MHz, CDCl₃) δ ppm7.29-7.41 (5 H, m), 6.00 (1 H, br. s.), 5.13 (2H, s), 3.63-3.87 (8 H,m), 2.84 (1 H, br. s.), 1.84-2.02 (2 H, m), 1.63-1.84 (2 H, m). Cap-189,Step h (Enantiomer-2): LC-MS: Anal. Calcd. for [M+H]⁺ C₁₈H₂₂NO₅ 332.15;found 332.2.

Cap-189, Step i

N₂ was bubbled through a solution of Cap-189, Step h (Enantiomer-2; 290mg, 0.875 mmol) in 10 mL of MeOH in a 500 mL hydrogenation bottle for 30mins. To the solution was added (S,S)-Me-BPE-Rh (9.74 mg, 0.018 mmol),and the mixture was then hydrogenated at 60 psi for 6 days. The mixturewas concentrated, and chiral analytical HPLC (CHIRALPAK® OJ column)indicated that there were a small amount of remaining starting materialand one major product. The residue was then separated by chiral HPLC(CHIRALPAK® OJ column, 21×250 mm, 10 um) eluting with 70% 0.1%diethylamine/Heptane-30% EtOH at 15 mL/min to afford Cap-189, Step i,(150 mg) as clear oil. LC-MS: Anal. Calcd. for [M+H]⁺ C₁₈H₂₄NO₅ 334.17;found 334.39. ¹H NMR (500 MHz, CDCl₃) δ ppm 7.28-7.41 (5 H, m),5.12-5.18 (1 H, m), 5.09 (2 H, s), 4.05 (1 H, t, J=10.07 Hz), 3.75 (3 H,s), 3.60-3.72 (2 H, m), 3.41-3.50 (2 H, m), 2.10 (1 H, br. s.),1.72-1.99 (6H, m).

Cap-189, Step j

To a solution of Cap-189, Step i (150 mg, 0.450 mmol) in 10 mL of MeOHin a hydrogenation bottle were added dimethyl dicarbonate (0.072 mL,0.675 mmol) and 10% Pd/C (23.94 mg, 0.022 mmol) under a cover ofnitrogen cover. The mixture was then hydrogenated on Parr-shaker at 45psi overnight. The mixture was filtered and the filtrate wasconcentrated to afford Cap-189, Step j (110 mg) as a clear oil. LC-MS:Anal. Calcd. for [M+H]⁺ C₁₂H₂₀NO₅ 258.13; found 258.19. ¹H NMR (500 MHz,CDCl₃) δ ppm 5.08 (1 H, d, J=9.16 Hz), 4.03 (1 H, t, J=10.07 Hz), 3.75(3 H, s), 3.60-3.72 (5 H, m), 3.46 (2 H, t, J=10.38 Hz), 2.11 (1 H, br.s.), 1.72-1.99 (6 H, m).

Cap-189

To a mixture of Cap-189, Step j (110 mg, 0.428 mmol) in 2 mL of THF and1 mL of water was added LiOH (0.641 mL, 1.283 mmol) (2 N aq.). Theresulting mixture was stirred at room temperature overnight. The mixturewas neutralized with a 1 N HCl aq. solution and extracted with EtOAc(3×). The combined organic layers were dried with MgSO₄ and concentratedto afford Cap-189 (100 mg) as a white solid. LC-MS: Anal. Calcd. for[M+Na]⁺ C₁₁H₁₇NNaO₅ 266.10; found 266.21. ¹H NMR (500 MHz, CDCl₃) δ ppm5.10 (1 H, d, J=9.16 Hz), 4.02 (1 H, t, J=10.07 Hz), 3.62-3.78 (5 H, m),3.49 (2 H, d, J=10.68 Hz), 2.07-2.22 (2 H, m), 1.72-1.98 (6 H, m).

Cap-190 (Diastereomeric Mixture)

Cap-190, Step a

To a mixture of cyclopent-3-enol (2.93 g, 34.8 mmol) and imidazole (5.22g, 77 mmol) in 30 mL of DMF at 0° C. was addedt-butyldimethylchlorosilane (6.30 g, 41.8 mmol). The resulting colorlessmixture was stirred at room temperature overnight. Hexanes and waterwere then added to the mixture and the two layers were separated. Theaqueous layer was extracted with EtOAc (2×) and the combined organiclayers were washed with brine, dried with MgSO₄ and concentrated. Thecrude product was purified by flash chromatography (silica gel, 2%EtOAc/Hex) to afford Cap-190, Step a (6.3 g) as a clear oil. ¹H NMR (500MHz, CDCl₃) δ ppm 5.65 (2 H, s), 4.49-4.56 (1 H, m), 2.56 (2 H, dd,J=15.26, 7.02 Hz), 2.27 (2 H, dd, J=15.26, 3.36 Hz), 0.88 (9 H, s), 0.06(6 H, s).

Cap-190,Step b

To a solution of Cap-190, Step a (2.3 g, 11.59 mmol) in 40 mL of CH₂Cl₂at 0° C. was added m-CPBA (5.60 g, 16.23 mmol) in 5 portions. Thereaction mixture was stirred at room temperature overnight. Hexanes andwater were then added to the mixture and the two layers were separated.The organic layer was washed with 50 mL aq. 10% NaHSO₃ and brine, driedwith MgSO₄ and concentrated. The crude product was purified by flashchromatography (silica gel, 3%-6% EtOAc/Hex) to afford Cap-190, Step b(1.42 g) and its trans diastereomer (0.53 g) as clear oils. Cap-190,Step b (cis): ¹H NMR (400 MHz, CDCl₃) δ ppm 4.39-4.47 (1 H, m), 3.47 (2H, s), 2.01-2.10 (2 H, m), 1.93-2.00 (2 H, m), 0.88 (9 H, s), 0.04 (6 H,s). Cap-190, Step b (trans): ¹H NMR (400 MHz, CDCl₃) δ ppm 4.04-4.14 (1H, m), 3.47 (2 H, s), 2.41 (2 H, dd, J=14.05, 7.28 Hz), 1.61 (2 H, dd,J=14.18, 6.90 Hz), 0.87 (9 H, s), 0.03 (6 H, s).

Cap-190, Step c

To a solution of (S)-1,2′-methylenedipyrrolidine (0.831 g, 5.39 mmol) in15 mL of benzene at 0° C. was added dropwise n-butyllithium (4.90 mL,4.90 mmol) (1 M in hexane). The solution turned bright yellow. Themixture was stirred at 0° C. for 30 min. Cap-190, Step b (cis-isomer;0.7 g, 3.27 mmol) in 10 mL of benzene was then added and the resultingmixture was stirred at 0° C. for 3 hours. EtOAc and sat. NH₄Cl aq.solution were added into the mixture, and the two layers were separated.The organic layer was washed with water and brine, dried with MgSO₄ andconcentrated. The crude product was purified by flash chromatography(silica gel, 15% EtOAc/Hex) to afford Cap-190, Step c (400 mg) as alight yellow oil. ¹H NMR (500 MHz, CDCl₃) δ ppm 5.84-5.98 (2 H, m),4.53-4.69 (2 H, m), 2.63-2.73 (1 H, m), 1.51 (1 H, dt, J=13.73, 4.43Hz), 0.89 (9 H, s), 0.08 (6 H, s).

Cap-190, Step d

To a solution of Cap-190, Step c (400 mg, 1.866 mmol), MeI (1.866 mL,3.73 mmol) (2 M in t-butyl methyl ether) in 5 mL of THF at 0° C. wasadded NaH (112 mg, 2.80 mmol) (60% in mineral oil). The resultingmixture was allowed to warm up to room temperature and stirred at roomtemperature overnight. The reaction was then quenched with water andextracted with EtOAc (3×). The combined organic layers were washed withbrine, dried with MgSO₄ and concentrated. The crude product was purifiedby flash chromatography (silica gel, 5% EtOAc/Hex) to afford Cap-190,Step d (370 mg) as light yellow oil. ¹H NMR (500 MHz, CDCl₃) δ ppm5.92-5.96 (1 H, m), 5.87-5.91 (1 H, m), 4.64-4.69 (1 H, m), 4.23-4.28 (1H, m), 3.32 (3 H, s), 2.62-2.69 (1 H, m), 1.54 (1 H, dt, J=13.12, 5.49Hz), 0.89 (9 H, s), 0.07 (5 H, d, J=1.83 Hz).

Cap-190, Step e

To a solution of Cap-190, Step d (400 mg, 1.751 mmol) in 10 mL of EtOAcin a hydrogenation bottle was added platinum(IV) oxide (50 mg, 0.220mmol). The resulting mixture was hydrogenated at 50 psi on Parr shakerfor 2 hours. The mixture was then filtered through CELITE®, and thefiltrate was concentrated to afford Cap-190, Step e (400 mg) as a clearoil. LC-MS: Anal. Calcd. for [M+H]⁺ C₁₂H₂₇O₂Si 231.18; found 231.3. ¹HNMR (500 MHz, CDCl₃) δ ppm 4.10-4.17 (1 H, m), 3.65-3.74 (1 H, m), 3.27(3 H, s), 1.43-1.80 (6 H, m), 0.90 (9 H, s), 0.09 (6 H, s).

Cap-190, Step f

To a solution of Cap-190, Step e (400 mg, 1.736 mmol) in 5 mL of THF wasadded TBAF (3.65 mL, 3.65 mmol) (1 N in THF). The color of the mixtureturned brown after several min., and it was stirred at room temperatureovernight. The volatile component was removed under vacuum, and theresidue was purified by flash chromatography (silica gel, 0-25%EtOAc/Hex) to afford Cap-190, Step f (105 mg) as light yellow oil. ¹HNMR (500 MHz, CDCl₃) δ ppm 4.25 (1 H, br. s.), 3.84-3.92 (1 H, m), 3.29(3 H, s), 1.67-2.02 (6 H, m).

Cap-190

Cap-190 was then synthesized from Cap-190, Step f according to theprocedure described for Cap-182. LC-MS: Anal. Calcd. for [M+Na]⁺C₁₀H₁₇NNaO₅ 254.10; found 254.3. ¹H NMR (500 MHz, CDCl₃) δ ppm 5.25 (1H, d, J=8.55 Hz), 4.27-4.41 (1 H, m), 3.81-3.90 (1 H, m), 3.69 (3 H, s),3.26 (3 H, s), 2.46-2.58 (1 H, m), 1.76-1.99 (3 H, m), 1.64-1.73 (1 H,m), 1.40-1.58 (1 H, m), 1.22-1.38 (1 H, m).

Cap-191 (Enantiomer-1)

Cap-191, Step a

To a solution of diisopropylamine (3 ml, 21.05 mmol) in THF (3 ml) at−78° C. under nitrogen was added n-butyl lithium (2.5 M in hexanes; 8.5ml, 21.25 mmol). The reaction was stirred at −78° C. for 10 min thenbrought up to 0° C. for 25 min. The reaction was cooled down again to−78° C., methyl tetrahydro-2H-pyran-4-carboxylate (3 g, 20.81 mmol) inTHF (3 ml) was added. The reaction was stirred at −78° C. for 15 minthen brought up to 0° C. for 30 min. The reaction was cooled down to−78° C., methyl iodide (1.301 ml, 20.81 mmol) was added. After theaddition, the cold bath was removed and the reaction was allowed toslowly warm up to ˜25° C. and stirred for 22 h. Ethyl acetate andaqueous HCl (0.1N) were added, and the organic layer was separated andwashed with brine and dried (MgSO₄), filtered, and concentrated invacuo. The residue was loaded on a Thomson's silica gel cartridgeeluting with 10% ethyl acetate/hexanes to afford a light yellow oil(2.83 g). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.73-3.66 (m, 2H), 3.66 (s,3H), 3.40-3.30 (m, 2H), 1.95-1.93 (dm, 1H), 1.92-1.90 (dm, 1H), 1.43(ddd, J=13.74, 9.72, 3.89, 2H), 1.18 (s, 3H).

Cap-191, Step b

To a solution of Cap-191, Step a (3 g, 18.96 mmol) in toluene (190 ml)at −78° C. under nitrogen was added diisobutylaluminum hydride (1.5M intoluene; 26.5 ml, 39.8 mmol) dropwise. The reaction was continued tostir at −78° C. for 1.5 h, and the bath was removed and was stirred for18 h. The reaction was quenched with MeOH (20 mL). HCl (1M, 150 mL) wasadded and the mixture was extracted with EtOAc (4×40 mL). The combinedorganic phases were washed with brine, dried (MgSO₄), filtered, andconcentrated in vacuo. The residue was purified with flashchromatography (silica gel; 40% ethyl acetate/hexanes) to afford acolorless oil (1.36 g). ¹H NMR (400 MHz, CDCl₃) δ ppm 3.77 (dt, J=11.73,4.55, 2H), 3.69-3.60 (m, 2H), 3.42 (s, 2H), 1.71-1.40 (bs, 1H) 1.59(ddd, J=13.74, 9.72, 4.39, 2H), 1.35-1.31 (m, 1H), 1.31-1.27 (m, 1H),1.06 (s, 3H).

Cap-191, Step c

To a solution of DMSO (5.9 ml, 83 mmol) in CH₂Cl₂ (85 ml) at −78° C.under nitrogen was added oxalyl chloride (3.8 ml, 43.4 mmol) and stirredfor 40 min. A solution of Cap-191, Step b (4.25 g, 32.6 mmol) in CH₂Cl₂(42.5 ml) was then added. The reaction was continued to be stirred at−78° C. under nitrogen for 2 h. The reaction was quenched with cold 20%K₂HPO₄ (aq) (10 mL) and water. The mixture was stirred at ˜25° C. for 15min, diluted with diethyl ether (50 mL) and the layers were separated.The aqueous layer was extracted with diethyl ether (2×50 mL). Thecombined organic layers were washed with brine, dried (MgSO₄), filtered,and concentrated in vacuo. The residue was taken up in CH₂Cl₂ (4 mL) andpurified with flash chromatography (silica gel, eluting with CH₂Cl₂) toafford a colorless oil (2.1 g). ¹H NMR (400 MHz, CDCl₃) δ ppm 9.49 (s.1H), 3.80 (dt, J=11.98, 4.67, 2H), 3.53 (ddd, J=12.05, 9.41, 2.89, 2H),1.98 (ddd, J=4.71, 3.20, 1.38, 1H), 1.94 (ddd, J=4.71, 3.20, 1.38, 1H),1.53 (ddd, J=13.87, 9.60, 4.14, 2H), 1.12 (s, 3H).

Cap-191,Step d

To a solution of Cap-191c (2.5 g, 19.51 mmol) in CHCl₃ (20 ml) undernitrogen at ˜25° C. was added (R)-2-amino-2-phenylethanol (2.94 g, 21.46mmol) and stirred for 5 h. The reaction was cooled to 0° C.,trimethylsilyl cyanide (3.8 ml, 30.4 mmol) was added dropwise. The coldbath was removed and the reaction was allowed to stir at ˜25° C. undernitrogen for 15.5 h. The reaction was treated with 3N HCl (20 mL) andwater (20 mL), and the product was extracted with CHCl₃ (3×50 mL). Thecombined organic layers were dried (NaSO₄), filtered, and concentratedin vacuo. The residue was purified with flash chromatography (silicagel; 40% ethyl acetate/hexanes) to afford two diastereomers: Cap-191,Step d1 (diastereomer 1) as a colorless oil which solidified into awhite solid upon standing (3 g). ¹H NMR (400 MHz, DMSO-d₆) δ ppm7.42-7.26 (m, 5H), 5.21 (t, J=5.77, 1H), 3.87 (dd, J=8.53, 4.52, 1H),3.61-3.53 (m, 1H), 3.53-3.37 (m, 5H), 3.10 (d, J=13.05, 1H), 2.65 (d,J=13.05, 1H), 1.64-1.55 (m, 1H), 1.55-1.46 (m, 1H), 1.46-1.39 (m, 1H),1.31-1.23 (m, 1H), 1.11 (s, 3H). LC-MS: Anal. Calcd. for [M+H]⁺C₁₆H₂₃N₂O₂: 275.18. found 275.20. Cap-191, Step d2 (diastereomer 2) as alight yellow oil (0.5 g). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.44-7.21 (m,5H), 4.82 (t, J=5.40, 1H), 3.82-3.73 (m, 1H), 3.73-3.61 (m, 3H),3.61-3.37 (m, 5H), 2.71 (dd, J=9.29, 4.77, 1H), 1.72-1.55 (m, 2H),1.48-1.37 (m, 1H), 1.35-1.25 (m, 1H), 1.10 (s, 3H). LC-MS: Anal. Calcd.for [M+H]⁺ C₁₆H₂₃N₂O₂: 275.18. found 275.20.

Cap-191,Step e

To a solution of Cap-191, Step d2 (diastereomer 2) (0.4472 g, 1.630mmol) in CH₂Cl₂ (11 ml) and MeOH (5.50 ml) at 0° C. under nitrogen wasadded lead tetraacetate (1.445 g, 3.26 mmol). The reaction was stirredfor 1.5 h, the cold bath was removed and stirring was continued for 20h. The reaction was treated with a phosphate buffer (pH=7; 6 mL) andstirred for 45 min. The reaction was filtered over CELITE®, washed withCH₂Cl₂ and the layers were separated. The aqueous layer was extractedwith CH₂Cl₂ (3×25 mL), and the combined organic layers was washed withbrine, dried (MgSO₄), filtered and concentrated in vacuo. The residuewas purified with flash chromatography (silica gel; 15% ethylacetate/hexanes) to afford the imine intermediate as a colorless oil(181.2 mg). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.55 (d, J=1.00, 1H),7.89-7.81 (m, 2H), 7.61-7.46 (m, 3H), 4.80 (d, J=1.00, 1H), 3.74 (tt,J=11.80, 4.02, 2H), 3.62-3.46 (m, 2H), 1.79-1.62 (m, 2H), 1.46-1.30 (m,2H), 1.15 (s, 3H).

The imine intermediate was taken up in 6N HCl (10 mL) and heated at 90°C. for 10 days. The reaction was removed from the heat, allowed to coolto room temperature and extracted with ethyl acetate (3×25 mL). Theaqueous layer was concentrated in vacuo to afford an off-white solid.The solid was taken up in MeOH and loaded on a pre-conditioned MCX (6 g)cartridge, washed with MeOH followed by elution with 2N NH₃/MeOHsolution and concentrated in vacuo to afford an off-white solid (79.8mg). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 14.33-13.51 (bs, 1H), 8.30 (bs,3H), 3.82-3.75 (m, 1H), 3.70 (dt, J=11.80, 4.02, 2H), 3.58-3.43 (m, 2H),1.76-1.60 (m, 2H), 1.47-1.36 (m, 1H), 1.36-1.27 (m, 1H), 1.08 (s, 3H).LC-MS: Anal. Calcd. for [M+H]⁺ C₈H₁₆NO₃: 174.11. found 174.19.

Cap-191 (Enantimer-1)

To a solution of Cap-191, Step e (0.0669 g, 0.386 mmol) and sodiumcarbonate (0.020 g, 0.193 mmol) in sodium hydroxide (1M aq.; 0.4 ml,0.40 mmol) at 0° C. was added methyl chloroformate (0.035 ml, 0.453mmol) dropwise. The reaction was removed from the cold bath and allowedto stir at ˜25° C. for 3 h. The reaction was washed with diethyl ether(3×20 mL). The aqueous layer was acidified with 12 N HCl (pH ˜1-2), andextracted with ethyl acetate (2×20 mL). The combined organic layers weredried (MgSO₄), filtered, and concentrated in vacuo to afford Cap-191 asa colorless film (66.8 mg). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 13.10-12.37(bs, 1H), 7.37 (d, J=9.04, 1H), 4.02 (d, J=9.29, 1H), 3.72-3.57 (m, 2H),3.56 (s, 3H), 3.54-3.44 (m, 2H), 1.65 (ddd, J=13.61, 9.72, 4.27, 1H),1.53 (ddd, J=13.68, 9.66, 4.27, 1H), 1.41-1.31 (m, 1H), 1.31-1.22 (m,1H), 1.00 (s, 3H). LC-MS: Anal. Calcd. for [M+Na]⁺ C₁₀H₁₇NO₅Na: 254.10;found 254.11.

Cap-192 (Enantiomer-2)

Cap-192 (Enantiomer-2) was prepared from Cap-191, Step d1 according tothe procedure described for the preparation of its enantiomer Cap-191.

Cap-193

Cap-193, Step a

To a solution of methyl2-(benzyloxycarbonylamino)-2-(dimethoxyphosphoryl)acetate (1.45 g, 4.2mmol) in DCM was added DBU (0.70 ml, 4.7 mmol). The reaction mixture wasstirred for 10 min, followed by addition of a solution of1,3-dimethoxypropan-2-one (0.5 g, 4.2 mmol) in DCM. The reaction mixturewas stirred at room temperature for 18 hrs. The reaction mixture wascharged to an 80 g silica gel cartridge which was eluted with an 18 mingradient of 0-70% EtOAc in hexane to afford Cap-193, Step a (0.8 g) as athick oil. ¹H NMR (400 MHz, MeOD) ppm 7.23-7.43 (5 H, m), 4.99-5.18 (2H, m), 4.16 (2 H, s), 4.06 (2 H, s), 3.66-3.78 (3 H, s), 3.26 (3 H, s),3.23 (3 H, s). LC-MS: Anal. Calcd. For [M+Na]⁺ C₁₆H₂₁NNaO₆: 346.14;found: 346.12.

Cap-193, Step b

A reaction mixture of ester Cap-193, Step a (0.5 g) and(+)-1,2-bis((2S,5S)-2,5-diethylphospholano)benzene(cyclooctadiene)rhodium(I) tetrafluoroborate (0.1 g) in MeOH was stirred under 55 psi of H₂ for18 hrs. The reaction mixture was concentrated to dryness. The residuewas charged to a 25 g silica gel cartridge and eluted with an 18 mingradient of 0-80% EtOAc in hexane to afford Cap-193, Step b (0.49 g) asa clear oil. LC-MS: Anal. Calcd. For [M+Na]⁺ C₁₆H₂₃NNaO₆: 348.15; found:348.19.

Cap-193, Step c

A reaction mixture of Cap-193, Step b (0.16 g), dimethyl dicarbonate(0.13 g) and 10% Pd/C (0.026 g) in EtOAc was stirred under H₂ at roomtemperature for 2 hrs. The reaction mixture was filtered andconcentrated to yield the methyl carbamate Cap-193, Step c. LC-MS: Anal.Calcd. For [M+Na]⁺ C₁₀H₁₉NNaO₆: 272.12; found: 272.07.

Cap-193

To a solution of ester Cap-193, Step c in THF (1 mL) and MeOH (0.25 mL)was added 1 N NaOH (1 mL). The reaction mixture was stirred at roomtemperature for 2 hrs. The reaction mixture was concentrated and dilutedwith EtOAc and 1 N HCl. The aqueous phase was extracted with EtOAc, andthe combined organic phase was washed with sat. NaCl, dried overanhydrous Na₂SO₄, filtered and concentrated to yield Cap-193 (0.082 g).¹H NMR (400 MHz, CDCl₃) 5.99 (1 H, d, J=8.56 Hz), 4.57 (1 H, dd, J=8.56,3.27 Hz), 3.67 (3 H, s), 3.49 (2 H, d, J=4.28 Hz), 3.45-3.44 (2 H, m),3.26-3.35 (6 H, m). LC-MS: Anal. Calcd. For [M+Na]⁺ C₉H₁₇NNaO₆: 258.11;found: 258.13.

Cap-194

Piperidine (1.0 mL, 10 mmol) was added to a solution of(S)-2-(9H-fluoren-9-yl)methoxy)carbonylamino)-4-methoxybutanoic acid(0.355 g, 1 mmol) in DMF (3 mL), and the mixture was stirred at rt for 3h. The volatiles were removed and the residue was partitioned betweensat. NaHCO₃ (aq.) (5 mL) and EtOAc (5 mL). The aqueous layer was furtherwashed with EtOAc and Et₂O. To the aqueous solution was added Na₂CO₃(212 mg, 2.0 mmol) followed by methyl chloroformate (0.16 mL, 2.0 mmol)and the reaction mixture was stirred at rt for 16 h. The reactionmixture was acidified with 1 N HCl (aq.) until pH <7 and then extractedwith EtOAc (2×10 mL). The combined organic layers were dried (Na₂SO₄),filtered and concentrated. The residue was purified by flash silicachromatography (EtOAc/hexanes, gradient from 20% to 70%) to yield(S)-4-methoxy-2-(methoxycarbonylamino)butanoic acid (Cap-194) (91.5 mg)as viscous colorless oil. LC-MS retention time=0.61 min; m/z 214[M+Na]⁺. (Column: PHENOMENEX® Luna 3.0×50 mm S10. Solvent A=90%Water:10% Methanol: 0.1% TFA. Solvent B=10% Water:90% Methanol: 0.1%TFA. Flow Rate=4 mL/min. Start % B=0. Final % B=100. Gradient Time=3min. Wavelength=220). ¹H NMR (400 MHz, chloroform-d) δ ppm 7.41 (br. s.,1 H), 5.74-6.02 (m, 1 H), 4.32-4.56 (m, 1 H), 3.70 (s, 3 H), 3.54 (t,J=5.0 Hz, 2 H), 3.34 (s, 3 H), 1.99-2.23 (m, 2 H).

EXAMPLES

Purity assessment and low resolution mass analysis were conducted on aShimadzu LC system coupled with Waters Micromass ZQ MS system. It shouldbe noted that retention times may vary slightly between machines. Unlessnoted otherwise, the LC conditions employed in determining the retentiontime (R_(t)) were:

Condition OL1

-   Column=XTERRA C18 S7 (4.6×30 mm)-   Start % B=0-   Final % B=100-   Gradient time=3 min-   Stop time=4 min-   Flow Rate=4 mL/min-   Wavelength=220 nm-   Solvent A=0.1% TFA in 10% methanol/90% water-   Solvent B=0.1% TFA in 90% methanol/10% water    Condition OL2-   Column=XTERRA C18 S7 (4.6×50 mm)-   Start % B=0-   Final % B=100-   Gradient time=3 min-   Stop time=4 min-   Flow Rate=4 mL/min-   Wavelength=220 nm-   Solvent A=0.1% TFA in 10% methanol/90% water-   Solvent B=0.1% TFA in 90% methanol/10% water    Condition OL3-   Column=XTERRA C18 S7 (3.0×50 mm)-   Start % B=0-   Final % B=100-   Gradient time=3 min-   Stop time=4 min-   Flow Rate=4 mL/min-   Wavelength=220 nm-   Solvent A=0.1% TFA in 10% methanol/90% water-   Solvent B=0.1% TFA in 90% methanol/10% water    Cond.-OL4-   Column=XTERRA 5 u (4.6×50 mm)-   Start % B=0-   Final % B=100-   Gradient time=2 min-   Stop time=3 min-   Flow Rate=4 mL/min-   Wavelength=220 nm-   Solvent A=0.2% H₃PO₄ in 10% methanol/90% H₂O-   Solvent B=0.2% H₃PO₄ in 90% methanol/10% H₂O    Cond.-MS-W1-   Column=XTERRA C18 S7 (3.0×50 mm)-   Start % B=0-   Final % B=100-   Gradient time=2 min-   Stop time=3 min-   Flow Rate=5 mL/min-   Wavelength=220 nm-   Solvent A=0.1% TFA in 10% methanol/90% H₂O-   Solvent B=0.1% TFA in 90% methanol/10% H₂O    Cond.-MS-W6-   Column=YMC-Pack Pro C-18 S3 (6.0×150 mm)-   Start % B=50-   Final % B=100-   Gradient time=15 min-   Stop time=16 min-   Flow Rate=1.5 mL/min-   Wavelength=220 nm-   Solvent A=0.1% TFA in 10% methanol/90% H₂O-   Solvent B=0.1% TFA in 90% methanol/10% H₂O    Cond.-D1-   Column=XTERRA C18 S7 (3.0×50 mm)-   Start % B=0-   Final % B=100-   Gradient time=3 min-   Stop time=4 min-   Flow Rate=4 mL/min-   Wavelength=220 nm-   Solvent A=0.1% TFA in 10% methanol/90% H₂O-   Solvent B=0.1% TFA in 90% methanol/10% H₂O    Cond.-D2-   Column=Phenomenex-Luna C18 S10 (4.6×50 mm)-   Start % B=0-   Final % B=100-   Gradient time=3 min-   Stop time=4 min-   Flow Rate=4 mL/min-   Wavelength=220 nm-   Solvent A=0.1% TFA in 10% methanol/90% H₂O-   Solvent B=0.1% TFA in 90% methanol/10% H₂O    Cond.-D3-   Column=Phenomenex Luna C18 S7 (3.0×50 mm)-   Start % B=0-   Final % B=100-   Gradient time=3 min-   Stop time=4 min-   Flow Rate=4 mL/min-   Wavelength=220 nm-   Solvent A=0.1% TFA in 10% methanol/90% H₂O-   Solvent B=0.1% TFA in 90% methanol/10% H₂O    Cond.-M3-   Column=XTERRA C18 3.0×50 mm S7-   Start % B=0-   Final % B=40-   Gradient time=2 min-   Stop time=3 min-   Flow Rate=5 mL/min-   Wavelength=220 nm-   Solvent A=0.1% TFA in 10% methanol/90% H₂O-   Solvent B=0.1% TFA in 90% methanol/10% H₂O    Cond-CB1-   Column=Primesphere C18-HC 4.6×30 mm-   Start % B=0-   Final % B=100-   Gradient Time=2 min-   Flow Rate=4 mL/min-   Wavelength=220-   Solvent A=10% CH₃CN-90% H₂O-5 mM NH₄OAc-   Solvent B=90% CH₃CN-10% H₂O-5 mM NH₄Oac    Cond.-JG1-   Column=XTERRA 3.0×50 mm S7-   Start % B=0-   Final % B=100-   Gradient time=3 min-   Stop time=4 min-   Flow Rate=4 mL/min-   Wavelength=220 nm-   Solvent A=0.1% TFA in 10% methanol/90% H₂O-   Solvent B=0.1% TFA in 90% methanol/10% H₂O    Cond.-JG2-   Column=XTERRA 3.0×50 mm S7-   Start % B=0-   Final % B=100-   Gradient time=4 min-   Stop time=5 min-   Flow Rate=4 mL/min-   Wavelength=220 nm-   Solvent A=0.1% TFA in 10% methanol/90% H₂O-   Solvent B=0.1% TFA in 90% methanol/10% H₂O    Cond.-JG3-   Column=Phenomenex-Luna 3.0×50 mm S10-   Start % B=0-   Final % B=100-   Gradient time=3 min-   Stop time=4 min-   Flow Rate=4 mL/min-   Wavelength=220 nm-   Solvent A=0.2% H₃PO₄ in 10% methanol/90% H₂O-   Solvent B=0.2% H₃PO₄ in 90% methanol/10% H₂O    Cond.-JG4-   Column=Phenomenex-Luna 3.0×50 mm S10-   Start % B=0-   Final % B=100-   Gradient Time=4 min-   Flow Rate=4 mL/min-   Wavelength=220-   Solvent A=10% methanol-90% H₂O-10 mm Ammonium Acetate-   Solvent B=90% methanol-10% H₂O-10 mm Ammonium Acetate    Condition IV-   Column=XTERRA 3.0×50 mm S7-   Start % B=0-   Final % B=100-   Gradient time=2 min-   Stop time=3 min-   Flow Rate=5 mL/min-   Wavelength=220 nm-   Solvent A=0.1% TFA in 10% methanol/90% H₂O-   Solvent B=0.1% TFA in 90% methanol/10% H₂O    Cond-RK1-   Column=XTerra MS C18-HC 4.6×50 mm, 5 um-   Start % B=10-   Final % B=100-   Gradient Time=2 min-   Flow Rate=4 mL/min-   Wavelength=220 nm-   Solvent A=H₂O-10 mM NH₄OAc-   Solvent B=CH₃CN-10 mM NH₄Oac    Cond.-J1-   Column=Phenomenex-Luna 4.6×50 mm S10-   Start % B=0-   Final % B=100-   Gradient time=2 min-   Stop time=3 min-   Flow Rate=4 mL/min-   Wavelength=220 nm-   Solvent A=0.1% TFA in 10% methanol/90% H₂O-   Solvent B=0.1% TFA in 90% methanol/10% H₂O    Cond.-J2-   Column=XTERRA 4.6×50 mm S5-   Start % B=0-   Final % B=100-   Gradient time=2 min-   Stop time=3 min-   Flow Rate=4 mL/min-   Wavelength=220 nm-   Solvent A=0.1% TFA in 10% methanol/90% H₂O-   Solvent B=0.1% TFA in 90% methanol/10% H₂O

Example OL-1

Example OL-1a

Ethyl malonyl chloride (2.5 mL, 19.5 mmol) was added slowly to asolution of benzoin (3.77 g, 17.8 mmol), pyridine (1.44 mL, 17.8 mmol)and dimethylaminopyridine (100 mg) in dichloromethane (30 mL) and keptat 10° C. in an ice-water bath for 30 min then allowed to warm toambient temperature for 2 h. The solvent was removed in vacuo followedby addition of acetic acid (60 mL) and ammonium chloride (6.25 g, 81.15mmol). The resulting mixture was heated to reflux temperature for 2 h,diluted with water and extracted with dichloromethane to yield an oilthat was purified by flash chromatography, eluting with ethylacetate/hexanes (10:90) to give Example OL-1a (2.93 g, 54% yield). ¹HNMR (CDCl₃, 500 MHz): δ 7.64 (m, 2 H), 7.58 (m, 2 H), 7.29-7.38 (m, 6H), 4.24 (q, J=7.1 Hz, 2 H), 3.93 (s, 2 H), 1.29 (t, J=7.1 Hz, 3 H).LC/MS (Cond. OL1): R_(t)=1.85 min; Anal. Calc. for [M+H]⁺ C₁₉H₁₈NO₃:308.12; found: 308.

Example OL-1b

Example OL-1a (0.35 g, 1.14 mmol) was added to cold fuming nitric acid(25 mL/g) keeping the temperature below 0° C. at all times. The yellowsolution was stirred at 0° C. for 30 min then allowed to warm to ambienttemperature, where it stirred for 1 h. The mixture was then poured ontoice and the aqueous suspension was neutralized with 5N sodium hydroxideand extracted with ethyl acetate. The organic layer was dried (MgSO₄),filtered and concentrated, to give Example OL-1b as a yellow solid (0.4g, 88% yield) which was used without further purification. ¹H NMR(DMSO-d₆, 500 MHz): δ 8.26 (dd, J=9.1, 2.2 Hz, 4 H), 7.82 (d, J=8.8 Hz,2 H), 7.75 (d, J=8.8 Hz, 2 H), 4.27 (q, J=7.1, 2 H), 3.98 (s, 2 H), 1.32(t, J=7.1 Hz, 3 H). LC/MS (Cond. OL2): R_(t)=2.04 min; Anal. Calc. for[M+H]⁺ C₁₉ H₁₆N₃O₇: 398.09; found: 398.

Example OL-1c

A catalytic amount of 20% palladium hydroxide on carbon (100 mg) inmethanol (2 mL) was added to Example OL-1b (0.15 g, 0.38 mmol) in ethylacetate/methanol (30:15 mL). The system was then placed under 1 atm ofhydrogen gas (balloon) and stirred at ambient temperature overnight. Thesuspension was filtered through a pad of Celite and concentrated invacuo. The product was purified by flash chromatography, eluting firstwith ethyl acetate/hexanes (50:50), then ethyl acetate and finallymethanol/ethyl acetate (5:95) to give Example OL-1c (85 mg (67% yield)as an off-white solid. ¹H NMR (DMSO-d₆, 500 MHz): δ 7.22 (d, J=8.5 Hz, 2H), 7.17 (d, J=8.5 Hz, 2 H), 6.57 (d, J=8.5 Hz, 2 H), 6.53 (d, J=8.5 Hz,2 H), 5.43 (bs, 2 H), 5.23 (bs, 2 H), 4.15 (q, J=7.2, 2 H), 3.96 (s, 2H), 1.21 (t, J=7.2 Hz, 3 H). LC/MS (Cond. OL2): R_(t)=0.91 min; Anal.Calc. for [M+H]⁺ C₁₉H₂₀N₃O₃: 338.14; found: 338.

Example OL-1d

2-Ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ, 0.13 g, 0.54 mmol)was added in one portion to a stirred suspension of Example OL-1c (0.08g, 0.24 mmol) and N-benzyloxycarbonyl-L-alanine (0.12 g, 0.52 mmol) inanhydrous dichloromethane (3 mL). The mixture was stirred at ambienttemperature for 15 h before the solvent was removed in vacuo andpurified by reverse phase preparative HPLC to afford Example OL-1d as awhite solid (0.13 g, 75% yield). ¹H NMR (DMSO-d₆, 500 MHz): δ 10.19 (s,1 H), 10.11 (s, 1 H), 7.68 (d, J=8.55 Hz, 2 H), 7.63 (dd, J=11.1, 8.1Hz, 4 H), 7.51 (d, J=8.55 Hz, 2 H), 7.47 (d, J=8.55 Hz, 2 H), 7.35 (m, 6H), 7.31 (m, 2 H), 7.25 (bs, 1 H), 7.18 (bs, 1 H), 5.02 (m, 4 H), 4.18(m, 4 H), 4.06 (s, 2 H), 1.29 (d, J=7.32 Hz, 6 H), 1.22 (t, J=7.17 Hz, 3H). LC/MS (Cond. OL3): R_(t)=1.80 min; Anal. Calc. for [M+H]⁺C₄₁H₄₂N₅O₉: 748.29; found: 748.

Example OL-1

A solution of lithium hydroxide (3.6 mg, 0.15 mmol) in water (2 mL) wasadded to a solution of Example OL-1d (75 mg, 0.094 mmol) intetrahydrofuran (2 mL) and the mixture was stirred at ambienttemperature for 3 h. The solvent was removed in vacuo and the remainingaqueous solution was extracted with ethyl acetate (2×5 mL). The combinedorganic layers were washed with sat. aqueous sodium bicarbonate and allthe aqueous layers were combined, acidified to pH=4 and extracted withethyl acetate. The organic layers were dried (MgSO₄), filtered andconcentrated. The residue was recrystallized fromdichloromethane/diethyl ether to afford Example OL-1 (32 mg, 40% yield)as a white solid. ¹H NMR (DMSO-d₆, 500 MHz): δ 13.02 (b.s, 1 H), 10.17(s, 1 H), 10.09 (s, 1 H), 7.66 (d, J=8.55 Hz, 2 H), 7.60 (m, 4 H), 7.49(d, J=8.55 Hz, 2 H), 7.45 (d, J=8.55 Hz, 2 H), 7.34 (m, 6 H), 7.29 (m, 2H), 7.25 (bs, 1 H), 7.18 (bs, 1 H), 5.00 (m, 4 H), 4.17 (t, J=7.32, 2H), 3.93 (s, 2 H), 1.27 (t, J=7.02 Hz, 6 H). LC/MS (Cond. OL1):R_(t)=1.72 min; Anal. Calc. for [M+H]⁺ C₃₉H₃₈N₅O₉: 720.26; found: 720.

Example OL-2

Prepared from Example OL-1c and Carbobenzyloxy-L-Proline, according tothe procedure described for Example OL-1d. This afforded Example OL-2(0.14 g, 95% yield) as an off-white solid. ¹H NMR (DMSO-d₆, 500 MHz): δ10.26 (s, 1 H), 10.18 (d, J=6.1 Hz, 1 H), 7.66 (m, 4 H), 7.51 (m, 4 H),7.37 (d, J=3.66 Hz, 4H), 7.32 (dd, J=8.4, 4.1 Hz, 1 H), 7.23 (m, 2 H),7.18 (t, J=7.2 Hz, 1 H), 7.12 (m, 2 H), 5.08 (m, 4 H), 4.94 (d, J=13.2Hz, 2 H), 4.37 (m, 2H), 4.17 (q, J=7.2 Hz, 2 H), 4.08 (d, J=3.7 Hz, 2H), 3.51 (m, 2 H), 3.45 (m, 2 H), 2.25 (m, 2 H), 1.91 (m, 6 H), 1.23 (t,J=7.0 Hz, 3 H). LC/MS (Cond. OL3): R_(t)=1.83 min; Anal. Calc. for[M+H]⁺ C₄₅H₄₆N₅O₉: 800.32; found: 800.

Example OL-3

Prepared from Example OL-2 according to the procedure described forExample OL-1. This gave Example OL-3 as an off-white solid (45 mg, 62%yield). ¹H NMR (DMSO-d₆, 500 MHz): δ 10.26 (s, 1 H), 10.18 (d, J=6.1 Hz,1 H), 7.66 (m, 4 H), 7.51 (m, 4 H), 7.37 (d, J=3.66 Hz, 4 H), 7.32 (dd,J=8.4, 4.1 Hz, 1 H), 7.23 (m, 2 H), 7.18 (t, J=7.2 Hz, 1 H), 7.12 (m, 2H), 5.08 (m, 4 H), 4.94 (d, J=13.2 Hz, 2 H), 4.37 (m, 2 H), 4.97 (d,J=3.7 Hz, 2 H), 3.51 (m, 2 H), 3.45 (m, 2 H), 2.25 (m, 2 H), 1.91 (m, 6H). LC/MS (Cond. OL3): R_(t)=1.72 min; Anal. Calc. for [M+H]⁺C₄₃H₄₂N₅O₉: 772.29; found: 772.

Example OL-4

Example OL-4a

Acetyl chloride (2 mL, 28.3 mmol) was added slowly to a solution ofbenzoin (5.47 g, 25.58 mmol), pyridine (2.1 mL, 25.8 mmol) andN,N′-dimethylaminopyridine (100 mg, catalytic) in dichloromethane (50mL) at 10° C. The mixture was stirred at 10° C. for 0.5 h and at ambienttemperature for 2 h. The solvent was then removed under reduced pressureand a mixture of ammonium acetate (9.7 g, 126 mmol) and glacial aceticacid (100 mL) was added to the residue. The resulting solution was thenstirred at reflux temperature for 2 h, diluted with water and extractedwith dichloromethane. The organic layer was washed with brine, dried(MgSO₄), filtered and concentrated. The yellow oil was purified by flashchromatography, eluting with ethyl acetate/hexanes (10:90) to affordExample OL-4a (5.65 g, 93% yield). ¹H NMR (CDCl₃, 500 MHz): δ 7.64 (d,J=7.0 Hz, 2 H), 7.58 (d, J=7.0 Hz, 2 H), 7.29-7.38 (m, 6 H), 2.55 (s, 3H). LC/MS (Cond. OL1): R_(t)=1.96 min; Anal. Calc. for [M+H]⁺ C₁₆H₁₄NO:236.1; found: 236.

Example OL-4b

Prepared from Example OL-4a, according to the procedure described forExample OL-1b. This afforded Example OL-4b (1.1 g, 80% yield) as ayellow solid. ¹H NMR (CDCl₃, 500 MHz): δ 8.31 (m, 4 H), 7.87 (d, J=8.1Hz, 2 H), 7.82 (d, J=9.2 Hz, 2 H), 2.58 (s, 3 H). LC/MS (Cond. OL2):R_(t)=2.10 min; Anal. Calc. for [M+H]⁺ C₁₆H₁₂N₃O₅: 326.07; found: 326.

Example OL-4c

Prepared from Example OL-4b, according to the procedure described forExample OL-1c. This afforded Example OL-4c (0.22 g, 68% yield) as anoff-white solid. ¹H NMR (CDCl₃, 500 MHz): δ 7.23 (d, J=8.3 Hz, 2 H),7.15 (d, J=8.3 Hz, 2 H), 6.57 (d, J=8.3 Hz, 2 H), 6.54 (d, J=8.3 Hz, 2H), 5.28 (bs, 4 H), 2.40 (s, 3 H). LC/MS (Cond. OL1): R_(t)=0.81 min;Anal. Calc. for [M+H]⁺ C₁₆H₁₆N₃O: 266.12; found: 266.

Example OL-4

Prepared from Example OL-4c, according to the procedure described forExample OL-1d. This afforded Example OL-4 (0.12 g, 75% yield) as anoff-white solid. ¹H NMR (CDCl₃, 500 MHz): δ 10.19 (s, 1 H), 10.11 (s, 1H), 7.68 (d, J=8.55 Hz, 2 H), 7.63 (dd, J=11.1, 8.1 Hz, 4 H), 7.51 (d,J=8.55 Hz, 2 H), 7.47 (d, J=8.55 Hz, 2 H), 7.36 (m, 6 H), 7.32 (m, 2 H),7.25 (bs, 1 H), 7.18 (bs, 1 H), 5.03 (m, 4 H), 4.20 (m, 2 H), 2.49 (s,3H), 1.30 (d, J=7.02 Hz, 6 H). LC/MS (Cond. OL1): R_(t)=1.84 min; Anal.Calc. for [M+H]⁺ C₃₈H₃₈N₅O₇: 676.27; found: 676.

Example OL-5

Prepared from Example OL-4c and Carbobenzyloxy-L-Proline, according tothe procedure described for Example OL-1d. This afforded Example OL-5(0.11 g, 63% yield) as an off-white solid. ¹H NMR (DMSO-d₆, 500 MHz): δ10.24 (s, 1 H), 10.16 (d, J=6.1 Hz, 1 H), 7.63 (m, 4 H), 7.49 (m, 4 H),7.37 (d, J=3.66 Hz, 4 H), 7.32 (m, 1 H), 7.23 (d, J=7.0 Hz, 2 H), 7.18(m, 1 H), 7.12 (m, 2 H), 5.08 (m, 3 H), 4.95 (d, J=13.2 Hz, 1H), 4.39(dd, J=7.9, 3.9 Hz, 1 H), 4.35 (dd, J=8.1, 2.9 Hz, 1 H), 3.52 (m, 2 H),3.45 (m, 2 H), 2.25 (m, 2 H), 1.90 (m, 6 H). LC/MS (Cond. 1): R_(t)=1.87min; Anal. Calc. for [M+H]⁺ C₄₂H₄₂N₅O₇: 728.3; found: 728.

Example OL-6

Example OL-6a

N-bromosuccinamide (0.76 g, 4.25 mmol) and benzoyl peroxide (0.17 g, 0.7mmol) were added in one portion to a solution of2-methyl-4,5-diphenyloxazole (1 g, 4.25 mmol) in carbon tetrachloride (5mL). The mixture was heated to reflux temperature for 6 h, the resultingsuccinimide was filtered-off and the solvent was removed in vacuo. Theremaining residue was purified by flash chromatography, eluting withethyl acetate/hexanes (5:95) to give Example OL-6a (0.95 g, 72% yield)as a brown solid. ¹H NMR (CDCl₃, 500 MHz): δ 7.79 (m, 2 H), 7.75 (m, 2H), 7.50-7.62 (m, 6 H), 4.38 (s, 2 H). LC/MS (Cond. OL1): R_(t)=1.93min; Anal. Calc. for [M+H]⁺ C₁₆H₁₃BrNO: 314.1; found: 314.

Example OL-6b

OL-6a (0.018 g, 0.57 mmol) and dimethylamine hydrochloride (93 mg, 1.14mmol) were added to a suspension of cesium carbonate (1 g, 2.87 mmol) inacetone (15 mL). The mixture was stirred at ambient temperature for 5 hand the solvent was removed in vacuo. The residue was partitionedbetween water and dichloromethane, and the organic layer was separated,dried (MgSO₄), filtered and concentrated. The desired product waspurified by flash chromatography, eluting with ethyl acetate/hexanes(60:40) to give Example OL-6b (0.13 g, 83% yield) as an off-white solid.¹H NMR (CDCl₃, 500 MHz): δ 7.65 (d, J=7.1 Hz, 2 H), 7.60 (d, J=7.1 Hz, 2H), 7.31-7.35 (m, 6 H), 3.72 (s, 2 H), 2.41 (s, 6 H). LC/MS (Cond. OL3):R_(t)=1.34 min; Anal. Calc. for [M+H]⁺ C₁₈H₁₉N₂O: 279.14; found: 279.

Example OL-6b

Prepared from Example OL-6a according to the procedure described forExample OL-1b. This afforded Example OL-6b (0.15 g, 87% yield) as ayellow solid. ¹H NMR (DMSO-d₆, 500 MHz): δ 8.13 (d, J=8.0, 2 H), 7.94(d, J=8.0 Hz, 2 H), 7.58 (d, J=8.0 Hz, 2 H), 7.29 (d, J=8.0 Hz, 2 H),3.82 (s, 2 H), 2.48 (s, 6 H). LC/MS (Cond. OL1): R_(t)=1.33 min; Anal.Calc. for [M+H]⁺ C₁₈H₁₇N₄O₅: 369.11; found: 369.

Example OL-6c

Prepared from Example OL-6b according to the procedure described forExample OL-1c. This afforded Example OL-6c (40 mg, 32% yield) as anoff-white solid. ¹H NMR (CDCl₃, 500 MHz): δ 7.43 (d, J=8.5, 2 H), 7.38(d, J=8.5 Hz, 2 H), 6.65 (d, J=8.5 Hz, 2 H), 6.62 (d, J=8.5 Hz, 2 H),3.66 (s, 2 H), 2.38 (s, 6 H). LC/MS (Cond. 1): R_(t)=0.15 min; Anal.Calc. for [M+H]⁺ C₁₈H₂₁N₄O: 309.16; found: 309.

Example OL-6

Prepared from Example OL-6c and(S)-1-(2-phenylacetyl)pyrrolidine-2-carboxylic acid according to theprocedure described for Example OL-1d. This afforded Example OL-6 (75mg, 89% yield). ¹H NMR (DMSO-d₆, 500 MHz): δ 10.25 (s, 1 H), 10.16 (s, 1H), 7.71 (d, J=8.85 Hz, 2 H), 7.66 (d, J=8.85 Hz, 2 H), 7.53 (m, 4 H),7.25 (m, 10 H), 4.64 (s, 2 H), 4.45 (dd, J=8.4 Hz, 3.8 Hz, 2 H), 3.70(d, J=3.36 Hz, 4 H), 3.63 (m, 4 H), 2.94 (s, 6 H), 2.16 (m, 2 H), 2.01(m, 2 H), 1.90 (m, 4 H). LC/MS (Cond. OL3): R_(t)=2.09 min; Anal. Calc.for [M+H]⁻ C₄₄H₄₆N₆O₅: 739.35. found (M+NH₄): 777. Anal. Calc. for[M−H]⁻ C₄₄H₄₇N₆O₅: 737.35; found: 737.

Example MS-1

Example MS-1a

2-Amino-1-(4-bromo-phenyl)-ethanone hydrochloride salt (2.5 g, 10.0mmol) was added portionwise to a cold (0° C.) solution of 4-nitrobenzoylchloride (1.85 g, 10.0 mmol) and pyridine (2.4 mL, 30.0 mmol) inmethylene chloride (100 mL). Upon completion of the addition, themixture was allowed to warm up to rt where it stirred for 2 h before itwas diluted with more methylene chloride and poured into 1N HCl. Theorganic phase was separated and concentrated down to yield Example MS-1a(3.6 g, 99%) as a white solid. ¹H NMR (DMSO-d₆, 500 MHz) δ 9.25 (t, 1H,J=5.5 Hz), 8.37 (d, 2 H, J=8.8 Hz), 8.13 (d, 2 H, J=8.8 Hz), 7.99 (d, 2H, J=8.4 Hz); R_(t)=1.35 min (Cond.-MS-W1).

Example MS-1b

Neat phosphorous oxychloride (40 mL) was added to Example MS-1a (3.1 g,8.56 mmol) and the mixture was heated at 80° C. for 16 h. Upon cooling,the reaction mixture was carefully poured into ice water and stirredvigorously to afford a yellow solid after filtration. The solid wastaken up in dichloromethane and neutralized with 10N NaOH. The organicphase was separated and evaporated to yield a solid which was trituratedwith methanol to furnish Example MS-1b (1.2 g, 41%) as a yellow solid.¹H NMR (DMSO-d₆, 500 MHz) δ 8.36 (d, 2 H, J=9.2 Hz), 8.29 (d, 2 H, J=9.2Hz), 8.00 (s, 1 H), 7.82 (d, 2 H, J=8.6 Hz), 7.71 (d, 2 H, J=8.6 Hz);¹³C NMR (DMSO-d₆, 125 MHz) δ 158.5, 151.0, 148.1, 132.0, 131.8, 127.0,126.2, 126.0, 125.6, 124.4, 122.1. R_(t)=1.87 min (Cond.-MS-W1); LCMS:Anal. Calc. for [M+H]^(+C) ₁₅H₁₀BrN₂O₃: 344.99; found: not obsd. LRMS:Anal. Calc. for [M+H]⁺ C₁₅H₁₀BrN₂O₃: 344.99, 346.99; found: 345.15,347.15.

Example MS-1c

Benzophenone imine (585 μL, 3.5 mmol, 1.2 eq.) was added to a mixture ofExample MS-1b (1.0 g, 2.9 mmol, 1.0 eq.), cesium carbonate (1.32 g, 4.0mmol, 1.4 eq.), Pd₂ dba₃ (53 mg, 0.058 mmol, 0.02 eq.), and(R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (BINAP, 72 mg,0.116 mmol, 0.04 equiv) in dioxane (10 mL) under an argon atmosphere.The reaction vessel was sealed and heated at 80° C. overnight. Themixture was cooled to ambient temperature and filtered through Celite,washing the filter pad with ether. The filtrate was concentrated invacuo to yield the crude imine (1.3 g) as a brown solid. A portion ofthe crude imine (1.0 g) was hydrolyzed with 1N HCl (5 mL) in THF (15 mL)for 20 min, and the resulting aniline was isolated by basifying with 10NNaOH and extractive workup with dichloromethane (3×). The crude anilinewas then acylated with N-phenacetyl-L-proline (450 mg, 3.0 mmol)following the procedure outlined for Example OL-1d. Flash chromatographyon silica gel (gradient elution with 0% methanol in dichloromethanefollowed by 5% methanol in dichloromethane) afforded MS-1c (800 mg, 66%)as a yellow solid. ¹H NMR (DMSO-d₆, 500 MHz) δ 10.2 (s, 1 H), 8.39 (d, 2H, J=7.3 Hz), 8.32 (d, 2 H, J=7.3 Hz), 7.88 (s, 1 H), 7.84 (d, 2 H,J=8.9 Hz), 7.75 (d, 2 H, J=8.9 Hz), 4.42 (m, 1 H), 3.51-3.64 (m, 2 H),2.15 (m, 1 H), 2.01 (s, 3 H), 1.93 (m, 3 H); ¹³C NMR (DMSO-d₆, 125 MHz)170.9, 168.4, 157.9, 152.1, 148.0, 139.8, 132.1, 126.8, 125.0, 124.4,124.0, 121.6, 119.4, 59.8, 47.6, 29.6, 24.3, 22.1. LC (Cond.-MS-W1):R_(t)=1.55 min; LC/MS: Anal. Calcd. for [M+H]⁺ C₂₂H₂₁N₄O₅: 421.15. found421.16. HRMS: Anal. Calc. for [M+H]⁺ C₂₂H₂₁N₄O₅: 421.1512. found:421.1501.

Example MS-1d

Example MS-1c (800 mg, 1.90 mmol) was subjected to catalytichydrogenation using 10% palladium on carbon (400 mg) in methanol (40 mL)under 1 atm of hydrogen for 16 h. The reaction was filtered throughCelite and concentrated to afford Example MS-1d (658 mg, 82%) as a lighttan solid. ¹H NMR (DMSO-d₆, 500 MHz) δ 10.1 (s, 1 H), 7.73 (d, 2 H,J=8.5 Hz), 7.70 (s, 2 H), 7.55 (s, 1 H), 6.66 (d, 2 H, J=8.5 Hz), 5.73(br s, 2 H), 4.40 (m, 1 H), 3.50-3.62 (m, 2 H), 2.13 (m, 1 H), 2.00 (s,3 H), 1.91 (m, 3 H); ¹³C NMR (DMSO-d₆, 125 MHz) 170.8, 168.4, 161.0,151.0, 149.0, 138.7, 127.3, 124.0, 122.6, 119.4, 113.5, 59.8, 47.6,29.6, 24.3, 22.1. LRMS: Anal. Calcd. for [M+H]⁺ C₂₂H₂₃N₄O₃: 391.18;found 391.2. HRMS: Anal. Calc. for [M+H]⁺ C₂₂H₂₃N₄O₃: 391.1770; found:391.1760.

Example MS-1

Prepared from Example MS-1d with N-phenacetyl-L-proline according to theprocedure described for Example OL-1d. This afforded Example MS-1 (26.6mg, 34%) as a yellow solid. ¹H NMR (MeOH-d₄, 500 MHz) δ 7.86 (d, 2 H,J=8.9 Hz), 7.65 (d, 2 H, J=8.9 Hz), 7.58 (m, 4 H), 7.43 (s, 1 H), 7.31(m, 5 H), 4.55 (m, 2 H), 3.97 (s, 2 H), 3.80, (m, 2 H), 3.61-3.77 (m, 4H), 2.23 (m, 2 H), 2.15 (s, 3 H), 2.02 (m, 2 H). LC (Cond.-MS-W6:R_(t)=11.00 min; 95% homogeneity index; LRMS: Anal. Calc. for [M+H]⁺C₃₅H₃₆N₅O₅: 606.27. found: 606.3. HRMS: Anal. Calc. for [M+H]⁺C₃₅H₃₆N₅O₅: 606.2716; found: 606.2738.

Example MS-2

Prepared from Example MS-1d and(2S,4R)-1-(benzyloxycarbonyl)-4-tert-butoxypyrrolidine-2-carboxylic acidaccording to the procedure described for Example OL-1d. This affordedExample MS-2 (23.1 mg, 26%) as an off-white solid. ¹H NMR (6:1MeOH-d₄/CDCl₃, 500 MHz) δ 7.99 (m, 2 H), 7.64-7.75 (m, 5 H), 7.49 (s, 1H), 7.30-7.36 (m, 2 H), 7.20 (m, 2 H), 7.08 (m, 2 H), 5.15 (m, 2H),4.45-4.54 (m, 2 H), 3.79 (m, 2 H), 3.61 (m, 2 H), 3.42 (m, 2 H), 2.27(m, 3 H), 2.17 (m, 2 H), 2.13 (s, 3 H), 1.22 (s, 9 H). LC (Cond.-MS-W6):R_(t)=13.83 min, 95% homogeneity index; LRMS: Anal. Calc. for [M+H]⁺C₃₉H₄₄N₅O₇: 694.33. found: 694.3. HRMS: Anal. Calc. for [M+H]⁺C₃₉H₄₄N₅O₇: 694.3240. found: 694.3264.

Example MS-3

Prepared from Example MS-1d and(2S,4R)-1-(benzyloxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acidaccording to the procedure described for Example OL-1d. This affordedExample MS-3 (29.8 mg, 37%) as a yellow solid. ¹H NMR (MeOH-d₄, 500 MHz)δ 7.99 (d, 2 H, J=8.9 Hz), 7.63-7.72 (m, 7 H), 7.53 (s, 1 H), 7.21 (d, 2H, J=7.0 Hz), 7.09 (d, 2 H, J=7.0 Hz), 5.15 (m, 2 H), 4.55 (m, 2 H),4.48 (m, 2 H), 3.71 (m, 2 H), 3.63 (m, 3 H), 2.31 (m, 2 H), 2.13 (s, 3H), 2.09 (m, 2 H). LC (Cond.-MS-W6): R_(t)=10.03 min; LRMS: Anal. Calc.for [M+H]⁺ C₃₅H₃₆N₅O₇: 638.26; found: 638.3. HRMS: Anal. Calc. for[M+H]⁺ C₃₅H₃₆N₅O₇: 638.2615; found: 638.2628.

Example MS-4

Prepared from Example MS-1d and(RS)-1-(benzyloxycarbonyl)pyrrolidine-3-carboxylic acid according to theprocedure described for Example OL-1d. This afforded Example MS-4 as amixture of diastereomers (25.6 mg, 32%) and as a yellow solid. ¹H NMR(MeOH-d₄, 500 MHz) δ 7.99 (d, 2H, J=8.9 Hz), 7.67-7.75 (m, 6H), 7.51 (s,1H), 7.37 (m, 5H), 5.13 (s, 2H), 4.53 (m, 1H), 3.61-3.72 (m, 5H), 3.45,(m, 1H), 3.21 (m, 1H), 2.17-2.31 (m, 3H), 2.13 (s, 3H), 2.05 (m, 3H). LC(Cond.-MS-W6): R_(t)=13.33 min; LRMS: Anal. Calc. for [M+H]⁺ C₃₅H₃₆N₅O₆:622.26; found: 622.2. HRMS: Anal. Calc. for [M+H]⁺ C₃₅H₃₆N₅O₆: 622.2666;found: 622.2500.

Example MS-5

Prepared from Example MS-1d and(RS)-5-oxo-1-(2-(thiophen-2-yl)ethyl)pyrrolidine-3-carboxylic acidaccording to the procedure described for Example OL-1d. This affordedExample MS-5 as a mixture of diastereomers (50.0 mg, 64%) and as agreenish-yellow solid. ¹H NMR (MeOH-d₄, 500 MHz) δ 7.98 (d, 2H, J=8.9Hz), 7.72 (d, 2H, J=8.9 Hz), 7.67 (m, 3H), 7.45 (s, 1H), 7.18 (m, 1H),6.88 (m, 3H), 4.54 (m, 1H), 3.71 (m, 1H), 3.54-3.62 (m, 5H), 3.09 (m,2H), 2.73 (d, 1H, J=6.7 Hz), 2.66 (d, 1H, J=9.8 Hz), 2.26 (m, 2H), 2.13(s, 3H), 2.02 (m, 3H). LC (Cond.-MS-W6): R_(t)=11.30 min; 95%homogeneity index; LRMS: Anal. Calc. for [M+H]⁺ C₃₃H₃₄N₅O₅S: 612.22.found: 612.2. HRMS: Anal. Calc. for [M+H]⁺ C₃₃H₃₄N₅O₅S: 612.2280. found:612.2280.

Example MS-6

Prepared from Example MS-1b according to the five step sequencedescribed for Example MS-1 (using N-acetyl-L-proline first instead ofN-phenacetyl-L-proline). This afforded Example MS-6 (43.3 mg, 12.3%overall yield) as a white solid. ¹H NMR (DMSO-d₆, 500 MHz) δ 10.24 (s, 1H), 10.17 (s, 1 H), 8.01 (d, 2 H, J=8.5 Hz), 7.69-7.78 (m, 7 H),7.18-7.32 (m, 5 H), 5.75 (s, 2 H), 4.44 (m, 2 H), 3.71, (s, 1 H),3.53-3.66 (m, 3 H), 2.16 (m, 2 H), 2.01 (s, 3 H), 1.92 (m, 6 H). LC(Cond.-MS-W6): R_(t)=11.29 min, 95% homogeneity index; LRMS: Anal. Calc.for [M+H]⁺ C₃₅H₃₆N₅O₅: 606.27; found: 606.3. HRMS: Anal. Calc. for[M+H]⁺ C₃₅H₃₆N₅O₅: 606.2717; found: 606.2721.

Example MS-7

Example MS-7a

Prepared from Example MS-1d and(S)-1-(tert-butoxycarbonyl)-2,5-dihydro-1H-pyrrole-2-carboxylic acidaccording to the procedure described for Example OL-1d. This affordedExample MS-7a (315 mg, 66%) as a light tan solid. ¹H NMR (DMSO-d₆, 500MHz) δ 10.37 (s, 1 H), 10.14 (s, 1 H), 8.04 (m, 2 H), 7.70-7.78 (m, 6H), 6.08 (m, 1 H), 5.86 (m, 1 H), 4.99 (m, 1 H), 4.41 (m, 1 H),4.10-4.19 (m, 2 H), 3.53-3.60 (m, 3 H), 2.14 (s, 3 H), 1.92 (m, 3 H),1.30 (s, 9 H). LC (Cond.-MS-W6): R_(t)=10.94 min; or LC/MS(Cond.-MS-W1): R_(t)=1.55 min; Anal. Calc. for [M+H]⁺ C₃₂H₃₆N₅O₆:586.27; found: 586.21. HRMS: Anal. Calc. for [M+H]⁺ C₃₂H₃₆N₅O₆:586.2665; found: 586.2674.

Example MS-7b

A cold (0° C.) solution of 4N HCl in dioxane (10 mL) was added toExample MS-7a (300 mg, 0.512 mmol) dissolved in dioxane (5 mL). Themixture was stirred rapidly at 0° C. for 0.5 h before it was allowed towarm up to room temperature. After 1 h at room temperature, the mixturewas concentrated down in vacuo to afford Example MS-7b (303 mg, 100+%)as a pale, yellow solid. ¹H NMR (MeOH-d₄, 400 MHz) δ 8.05-7.99 (m, 2 H),7.77-7.65 (series of m, 6 H), 7.52 and 7.49 (2s, 1 H), 6.14-6.06 (m, 2H), 5.22 (br s, 1 H), 4.59-4.56 and 4.53-4.50 (2m, 1 H), 4.31-4.26 (m, 1H), 4.19-4.15 (m, 1 H), 3.73-3.68 (m, 1 H), 3.65-3.59 (m, 1 H),2.29-2.26 (m, 1 H), 2.11 and 1.99 (2s, 3 H), 2.10-2.00 (m, 3 H). LC/MS(Cond.-D1): R_(t)=1.61 min; Anal. Calc. for [M+H]⁺ C₂₇H₂₈N₅O₄: 486.21;found: 486.27. HRMS: Anal. Calc. for [M+H]⁺ C₂₇H₂₈N₅O₄: 486.2141; found:486.2125.

Example MS-7

Prepared from Example MS-7b and thiophene-2-carboxylic acid according tothe procedure described for Example D-57. This afforded Example MS-7(32.6 mg, 57%) as a tan solid. ¹H NMR (MeOH-d₄, 500 MHz) δ 8.04-8.02 (m,2 H), 7.79-7.67 (series of m, 8 H), 7.54-7.52 (m, 1 H), 7.22-7.20 (m, 1H), 6.22-6.20 (m, 1 H), 6.01-6.00 (m, 1 H), 5.51 (br s, 1 H), 4.73-4.40(m, 1 H), 4.59-4.53 (2m, H), 3.74-3.70 (m, 1 H), 3.66-3.62 (m, 2 H),2.31-2.27 (m, 1 H), 2.13 and 2.01 (2s, 3 H), 2.12-2.03 (m, 3 H). LC/MS(Cond.-D1): R_(t)=2.04 min; Anal. Calc. for [M+H]⁺ C₃₂H₃₀N₅O₅S: 596.20.found: 596.14. HRMS: Anal. Calc. for [M+H]⁺ C₃₂H₃₀N₅O₅S: 596.1968.found: 596.1963.

Example D-1

Prepared from Example MS-7b and 2-(thiophen-2-yl)acetic acid accordingto the procedure described for Example D-57. This afforded Example D-1(35.4 mg, 61%) as a tannish-orange solid. ¹H NMR (MeOH-d₄, 500 MHz) δ8.03-7.88 (2m, 2 H), 7.76-7.67 (series of m, 3 H), 7.61 (s, 3 H), 7.52,7.51 and 7.45 (3s, 1 H), 7.30-7.25 (m, 1 H), 7.02-6.90 (3m, 2 H),6.15-6.12 (m, 1 H), 5.93-5.90 (2m, 1 H), 5.33-5.28 (2m, 1 H), 4.60-4.39(m, 3 H), 4.08-3.98 (m, 2 H), 3.74-3.71 (m, 1 H), 3.65-3.63 (m, 1 H),2.30-2.26 (m, 1H), 2.15, 2.14 and 2.01 (3s, 3 H), 2.13-2.03 (m, 3 H).LC/MS (Cond.-D1): R_(t)=2.08 min; Anal. Calc. for [M+H]⁺ C₃₃H₃₂N₅O₅S:610.21; found: 610.17. HRMS: Anal. Calc. for [M+H]⁺ C₃₃H₃₂N₅O₅S:610.2124; found: 610.2126.

Example D-2

Prepared from Example MS-7b and 2-ethylbenzoic acid according to theprocedure described for Example D-57. This afforded Example D-2 (36.3mg, 61%) as a pale, yellow solid. ¹H NMR (MeOH-d₄, 500 MHz) δ 8.07-7.68(series of m, 7 H), 7.56-7.49 (m, 2 H), 7.42-7.37 (m, 2 H), 7.31-7.23(m, 2 H), 6.22-5.85 (4m, 2 H), 5.48-5.47 (m, 1 H), 4.57-4.53 (m, 2 H),4.22-4.19 (m, 1 H), 4.04-4.01 (m, 1 H), 3.74-3.72 (m, 1 H), 3.65-3.60(m, 1 H), 2.83-2.79 (m, 1 H), 2.72-2.67 (m, 1 H), 2.30-2.27 (m, 1 H),2.14, 2.13 and 2.01 (3s, 3 H), 2.10-2.02 (m, 3 H), 1.26-1.19 (m, 3 H).LC/MS (Cond.-D1): R_(t)=2.22 min; Anal. Calc. for [M+H]⁺ C₃₆H₃₆N₅O₅:618.27; found: 618.22. HRMS: Anal. Calc. for [M+H]⁺ C₃₆H₃₆N₅O₅:618.2717; found: 618.2746.

Example D-3

Prepared from Example MS-7b and isoxazole-5-carboxylic acid according tothe procedure described for Example D-57. This afforded Example D-3(28.3 mg, 51%) as a tan solid. ¹H NMR (MeOH-d₄, 500 MHz) δ 8.57-8.47(2m, 1 H), 8.05-7.98 (m, 2 H), 7.79-7.64 (2m, 7 H), 7.54-7.51 (m, 1 H),7.08 and 7.00 (2s, 1 H), 6.22-6.20 (m, 1 H), 6.05-6.00 (2m, 1 H),5.90-5.50 (2m, 1 H), 4.59-4.53 (m, 2 H), 3.73-3.70 (m, 1 H), 3.65-3.63(m, 1 H), 2.31-2.26 (m, 1 H), 2.14 and 2.01 (2s, 3 H), 2.13-2.02 (m, 3H). LC/MS (Cond.-D1): R_(t)=1.88 min; Anal. Calc. for [M+H]⁺ C₃M29N606:581.21; found: 581.16. HRMS: Anal. Calc. for [M+H]⁺ C₃₁H₂₉N₆O₆:581.2149; found: 581.2171.

Example D-4

Example D-4a

Sulfuric acid (10 mL) was cooled to 0° C. and 2,5-diphenyloxazole (12 g,54 mmol) was added in two portions. To this orange suspension was addeddropwise a 1:1 solution of HNO₃/H₂SO₄ concentrated acids over 10 min.The reaction was stirred for 2.5 h at 0° C. and poured onto chopped iceand filtered. The product was washed with water and diethyl ether anddried to afford Example D-4a (5 g, 30%) as a bright, yellow solid. Thecold filtrate was extracted with EtOAc (300 mL) and the organic extractwas decanted into a clean flask. Hexanes (60 mL) was then added and themixture was allowed to stand idle at rt for 16 h to afford a second cropof Example D-4a (7 g, 42%). ¹HNMR (DMSO-d₆, 300 MHz) δ 8.40 (d, J=3.3Hz, 4H), 8.36 (m, 2H), 8.29 (s, 1H), 8.18 (d, J=8.8 Hz, 2H). LC/MS(Cond.-D2): R_(t)=2.87 min; Anal. Calc. for [M+H]⁺ C₁₅H₉N₃O₅: 312.05;found: 312.13.

Example D-4b

A suspension of Example D-4a (9.83 g, 31.6 mmol) in methanol (100 mL)and ethyl acetate (100 mL) was subjected to balloon hydrogenation over20% Pd(OH)₂/C (1.0 g) for 6 h at ambient temperature before it wassuction-filtered through Celite and concentrated down in vacuo to yieldthe crude product as a reddish solid. The solid was dissolved in hotmethanol and the solution was cooled to ambient temperature and theprecipitate which formed on cooling was suctioned-filtered to furnishcrop 1 of Example D-4b (1.70 g, 21%) as a brick-colored solid. Thefiltrate was concentrated in vacuo and this residue was dissolved againin a minimal amount of hot methanol to afford crop 2 of Example D-4b(2.90 g, 37%) as a reddish-brown solid after cooling to rt andsuction-filtration. This filtrate was concentrated down in vacuo and theresidue was subjected to flash chromatography on silica gel (gradientelution first with 50% ethyl acetate in hexanes followed by 75% ethylacetate in hexanes and finally 100% ethyl acetate) to yield crop 3 ofExample D-4b (2.3 g, 29%) as an orange solid after concentration of theeluant to ¼ volume and suction-filtration of the precipitate. ¹HNMR(DMSO-d₆+D₂O, 300 MHz) δ 7.72 (d, J=8.4 Hz, 2H), 7.54 (d, J=8.4 Hz, 2H),7.40 (s, 1H), 6.83 (d, J=8.05 Hz, 2H), 6.69 (d, J=8.05 Hz, 2H). LC/MS(Cond.-D3): R_(t)=1.17 min; Anal. Calc. for [M+H]⁺ C₁₅H₁₃N₃O: 252.11;found: 252.05.

Example D-4c

To a mixture of Example D-4b (3.0 g, 11.94 mmol) and Boc-L-proline (5.27g, 24.47 mmol) in dichloromethane (120 ml) was added EEDQ (6.20 g, 25.07mmol). The mixture was stirred at 25° C. for 2 h before additionalBoc-L-proline (2.64 g) and EEDQ (3.1 g) were added. After stirring foran additional 1.5 h at rt, most of the solvent was removed in vacuo andthe residue was loaded onto a silica gel column and was eluted with 50%ethyl acetate in hexanes) to afford Example D-4c as an orange solid (6.2g, 80%). ¹H NMR (400 MHz, DMSO-d₆) δ 10.28 (s, 1H), 10.17 (s, 1H),8.04-8.02 (m, 2H), 7.79-7.68 (m, 7H), 4.28-4.19 (m, 2H), 3.46-3.32 (m,4H), 2.25-2.17 (m, 2H), 1.95-1.80 (2m, 6H), 1.41 and 1.27 (2s, 18H);LC/MS (Cond. D2): R_(t)=2.95 min; Anal. Calc. for [M+H]⁺ C₃₅H₄₄N₅O₂:646.63; found: 646.51. HRMS: Anal. Calc. for [M+H]⁺ C₃₅H₄₄N₅O₂:646.3241; found: 646.3254.

Example D-4d

To a cold (0° C.) solution of Example D-4c (6.2 g, 9.60 mmol) inmethanol (5 mL) was added 4N HCl in dioxane (30 ml). The reactionmixture was allowed to warm up to 25° C. where it stirred for 4 h beforeit was diluted with ether (100 ml) and filtered. The precipitate waswashed with ether (2×100 ml) and dried under high vacuum to affordExample D-4d as an orange solid (4.91 g, 98%). ¹H NMR (400 MHz, DMSO-d₆)δ 10.39-10.38 and 9.64-9.62 (2m, 2H), 8.09 (s, 1H), 7.93-7.02 (series ofm, 8H), 4.78-4.75 and 4.48-4.45 (2m, 2H), 3.34-3.28 (m, 2H), 3.23-3.18(m, 2H), 2.40-2.30 (m, 2H), 2.10-1.80 (2m, 6H); LC/MS (Cond.-D2):R_(t)=1.64 min; Anal. Calc. for [M+H]⁺ C₂₅H₂₈N₅O₃: 446.22. found:446.50. HRMS: Anal. Calc. for [M+H]⁺ C₂₅H₂₈N₅O₃: 446.2192; found:446.2207.

Example D-4

Prepared from Example D-4d and(RS)-2-(dimethylamino)-2-(2-fluorophenyl)acetic acid (i.e. Cap-38)according to the procedure described for Example D-57. This affordedExample D-4 (51.3 mg, 66%) as a pale, yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ 10.53-10.26 (m, 3H), 8.07-8.02 (m, 2H), 7.82-7.62 (3m, 8H),7.51-7.40 (m, 4H), 5.81-5.79 and 5.74-5.73 (2m, 2H), 4.60-4.55 and4.50-4.47 (2m, 2H), 4.03-3.93 (m, 1H), 3.80-3.73 (m, 1H), 3.17-3.12 (m,1H), 3.01-2.95 (m, 1H), 2.85-2.78 (m, 1H), 2.54 and 2.50 (2s, 12H),2.31-2.11 (m, 2H), 2.06-1.75 (3m, 5H); LC/MS (Cond.-D1): R_(t)=1.84 min;Anal. Calc. for [M+H]^(+C) ₄₅H₄₈F₂N₂O₅: 804.37; found: 804.36. HRMS:Anal. Calc. for [M+H]⁺ C₄₅H₄₈F₂N₂O₅: 804.3685; found: 804.3721.

Examples D-5 to D-33

Examples D-5 to D-33 were prepared from Example D-4-d and 2.0 eq. of theappropriate, commercially-available or synthesized carboxylic acidaccording to the procedure described for Example D-57. Purification ofthe final targets was accomplished using a Shimadzu reverse phasepreparative HPLC instrument (solvent systems: H₂O/MeOH/TFA orH₂O/ACN/TFA) and the final products were isolated as TFA salts. Thecoupling partner (ROH) obtained from commercial sources unless otherwisenoted.

R_(t) (LC-Cond.); % Coupling homogeneity index; Example Protocol R MSdata D-5  HATU, DIPEA, DMF

  two diastereomers 1.86 and 1.93 min (Cond.-D1); LCMS: Anal. Calc. for[M + H]⁺ C₄₅H₄₆F₄N₇O₅: 840.35; found: 840.39. HRMS: Anal. Calc. for [M +H]⁺ C₄₅H₄₆F₄N₇O₅: 840.3497; found: 840.3502. D-6  HATU, DIPEA, DMF

  predominantly one diastereomer contaminated with D-5 1.92 min(Cond.-D1); LCMS: Anal. Calc. for [M + H]⁺ C₄₅H₄₆F₄N₇O₅: 840.35; found:840.40. HRMS: Anal. Calc. for [M + H]⁺ C₄₅H₄₆F₄N₇O₅: 840.3497; found:840.3491. D-7  HATU, DIPEA, DMF

  predominantly one diastereomer different from D-5 and D-6 1.98 min(Cond.-D1); LCMS: Anal. Calc. for [M + H]⁺ C₄₅H₄₆F₄N₇O₅: 840.38; found:840.40. HRMS: Anal. Calc. for [M + H]⁺ C₄₅H₄₆F₄N₇O₅: 840.3497; found:840.3480. D-8  HATU, DIPEA, DMF

2.51 min (Cond.-D2); LCMS: Anal. Calc. for [M + H]⁺ C₅₁H₆₀N₉O₅: 878.47;found: 878.72. HRMS: Anal. Calc. for [M + H]⁺ C₅₁H₆₀N₉O₅: 878.4717;found: 878.4718. D-9  HATU, DIPEA, DMF

3.43 min (Cond.-D2); LCMS: Anal. Calc. for [M + H]⁺ C₄₉H₄₈F₄N₉O₇:950.36; found: 950.81. HRMS: Anal. Calc. for [M + H]⁺ C₄₉H₄₈F₄N₉O₇:950.3613; found: 950.3582. D-10 HATU, DIPEA, DMF

2.36 min (Cond.-D2); LCMS: Anal. Calc. for [M + H]⁺ C₃₅H₃₄N₇O₇S₂:728.20; found: 728.40. HRMS: Anal. Calc. for [M + H]⁺ C₃₅H₃₄N₇O₇S₂:728.1961; found: 728.1926. D-11 HATU, DIPEA, DMF

1.82 min (Cond.-D2); LCMS: Anal. Calc. for [M + H]⁺ C₃₇H₄₁N₉O₇: 722.31;found: 722.51. HRMS: Anal. Calc. for [M + H]⁺ C₃₇H₄₁N₉O₇: 722.3051;found: 722.3056. D-12 HATU, DIPEA, DMF

2.50 min (Cond.-D2); LCMS: Anal. Calc. for [M + H]⁺ C₄₃H₄₁N₇O₁₁: 836.33;found: 836.56. HRMS: Anal. Calc. for [M + H]⁺ C₄₃H₄₇N₇O₁₁: 836.3255;found: 836.3248. D-13 HATU, DIPEA, DMF

1.87 min (Cond.-D2); LCMS: Anal. Calc. for [M + H]⁺ C₄₃H₄₁N₉O₇: 794.31;found: 794.50. HRMS: Anal. Calc. for [M + H]⁺ C₄₃H₄₁N₉O₇: 794.3051;found: 794.3060. D-14 HATU, DIPEA, DMF

1.92 min (Cond.-D2); LCMS: Anal. Calc. for [M − H]⁻ C₃₉H₃₆N₇O₇: 714.27;found: 714.35. HRMS: Anal. Calc. for [M − H]⁻ C₃₉H₃₆N₇O₇: 714.2676;found: 714.2681. D-15 HATU, DIPEA, DMF

2.41 min (Cond.-D2); LCMS: Anal. Calc. for [M + H]⁺ C₄₉H₅₁N₇O₉: 880.37;found: 880.62. HRMS: Anal. Calc. for [M + H]⁺ C₄₉H₅₁N₇O₉: 880.3670;found: 880.3632. D-16 HATU, DIPEA, DMF

1.95 min (Cond.-D2); LCMS: Anal. Calc. for [M + H]⁺ C₄₃H₄₁N₉O₇: 794.31;found: 794.50. HRMS: Anal. Calc. for [M + H]⁺ C₄₃H₄₁N₉O₇: 794.3051;found: 794.3082. D-17 HATU, DIPEA, DMF

1.86 min (Cond.-D2); LCMS: Anal. Calc. for [M + H]⁺ C₄₃H₄₁N₉O₇: 794.31;found: 794.50. HRMS: Anal. Calc. for [M + H]⁺ C₄₃H₄₁N₉O₇: 794.3051;found: 794.3066. D-18 HATU, DIPEA, DMF

2.63 min (Cond.-D2, S5 instead); LCMS: Anal. Calc. for [M + H]⁺C₄₇H₅₁N₇O₉: 856.37; found: 856.32. HRMS: Anal. Calc. for [M + H]⁺C₄₇H₅₁N₇O₉: 856.3670; found: 856.3699. D-19 HATU, DIPEA, DMF

2.35 min (Cond.-D2); LCMS: Anal. Calc. for [M + H]⁺ C₄₇H₅₂Cl₂N₇O₇:896.33; found: 896.46. HRMS: Anal. Calc. for [M + H]⁺ C₄₇H₅₂Cl₂N₇O₇:896.3305; found: 896.3318. D-20 HATU, DIPEA, DMF

2.68 min (Cond.-D1); LCMS: Anal. Calc. for [M + H]⁺ C₃₅H₄₀N₅O₅: 610.30;found: 610.56. HRMS: Anal. Calc. for [M + H]⁺ C₃₅H₄₀N₅O₅: 610.3029;found: 610.3048. D-21 HATU, DIPEA, DMF

  stereochemical composition undetermined 2.56 min (Cond.-D2); LCMS:Anal. Calc. for [M + H]⁺ C₅₁H₅₈N₇O₅: 848.45; found: 848.54. HRMS: Anal.Calc. for [M + H]⁺ C₅₁H₅₈N₇O₅: 848.4499; found: 848.4464. D-22 HATU,DIPEA, DMF

  mixture of diastereomers stereochemical composition undetermined 2.66and 2.84 min (Cond.-D2); LCMS: Anal. Calc. for [M + H]⁺ C₅₁H₇₀N₇O₅:860.54; found: 860.61. HRMS: Anal. Calc. for [M + H]⁺ C₅₁H₇₀N₇O₅:860.5438; found: 860.5468. D-23 HATU, DIPEA, DMF

  stereochemical composition undetermined 2.79 min (Cond.-D2); LCMS:Anal. Calc. for [M + H]⁺ C₅₁H₅₄N₇O₇: 876.41; found: 876.45. HRMS: Anal.Calc. for [M − H]⁻ C₅₁H₅₂N₇O₇: 874.3928; found: 874.3950. D-24 HATU,DIPEA, DMF

  stereochemical composition undetermined 2.13 min (Cond.-D2); LCMS:Anal. Calc. for [M + H]⁺ C₃₇H₄₃N₇O₇: 696.31; found: 696.37. HRMS: Anal.Calc. for [M + H]⁺ C₃₇H₄₃N₇O₇: 696.3146; found: 696.3160. D-25 HATU,DIPEA, DMF

  stereochemical composition undetermined 2.41 min (Cond.-D2); LCMS:Anal. Calc. for [M + H]⁺ C₄₁H₅₁N₇O₇: 752.38; found: 752.42. HRMS: Anal.Calc. for [M + H]⁺ C₄₁H₅₁N₇O₇: 752.3772; found: 752.3766. D-26 HATU,DIPEA, DMF

3.57 min (Cond.-D2); LCMS: Anal. Calc. for [M + H]⁺ C₅₁H₄₆Cl₄N₇O₇:1010.78; found: 1010.69. D-27 HATU, DIPEA, DMF

3.01 min (Cond.-D2); LCMS: Anal. Calc. for [M + H]⁺ C₄₅H₅₈N₇O₉: 840.43;found: 840.70. HRMS: Anal. Calc. for [M + H]⁺ C₄₅H₅₆N₇O₉: 838.4140;found: 838.4142 D-28 HATU, DIPEA, DMF

2.99 min (Cond.-D2); LCMS: Anal. Calc. for [M + H]⁺ C₄₅H₅₈N₇O₉: 840.43;found: 840.46. HRMS: Anal. Calc. for [M + H]⁺ C₄₅H₅₆N₇O₉: 838.4140;found: 838.4148. D-29 HATU, DIPEA, DMF

  stereochemical composition undetermined 3.07 min (Cond.-D2); LCMS:Anal. Calc. for [M + H]⁺ C₄₇H₆₂N₇O₉: 868.46; found: 868.50. HRMS: Anal.Calc. for [M − H]⁻ C₄₇H₆₀N₇O₉: 866.4453; found: 866.4488. D-30 HATU,DIPEA, DMF

  stereochemical composition undetermined 3.16 min (Cond.-D2); LCMS:Anal. Calc. for [M + H]⁺ C₄₇H₆₂N₇O₉: 868.46; found: 868.56. HRMS: Anal.Calc. for [M − H]⁻ C₄₇H₆₀N₇O₉: 866.4453; found: 866.4460. D-31 HATU,DIPEA, DMF

  stereochemical composition undetermined 3.06 min (Cond.-D2); LCMS:Anal. Calc. for [M + H]⁺ C₄₇H₅₈N₇O₉: 864.43; found: 864.72. HRMS: Anal.Calc. for [M + H]⁺ C₄₇H₅₈N₇O₉: 864.4296; found: 864.4313. D-32 HATU,DIPEA, DMF

  stereochemical composition undetermined 3.44 min (Cond.-D2); LCMS:Anal. Calc. for [M + H]⁺ C₅₉H₇₀N₇O₉: 1020.52; found: 1020.77. HRMS:Anal. Calc. for [M − H]⁻ C₅₉H₆₈N₇O₉: 1018.5079; found: 1018.5067. D-33HATU, DIPEA, DMF

  mixture of diastereomers stereochemical composition undetermined 3.39and 3.54 min (Cond.-D2); LCMS: Anal. Calc. for [M + H]⁺ C₅₉H₇₀N₇O₉:1020.52; found: 1020.82. HRMS: Anal. Calc. for [M − H]⁻ C₅₉H₆₈N₇O₉:1018.5079; found: 1018.5059.

Examples D-34 to D-37

Examples D-34 to D-37 were prepared from their respective Boc-protected(D-27, D-28, D-29/D-30 and D-32/D-33) analogs according to the proceduredescribed for Example MS-7b. The final targets were isolated as HClsalts.

R_(t) (LC-Cond.); % Reaction homogeneity Example Protocol R₁ and R₂index; MS data D-34 4N HCl in dioxane R₁ = R₂ =  

1.86 min (Cond.- D2); LCMS: Anal. Calc. for [M + H]⁺ C₃₅H₄₂N₇O₅: 640.32;found: 640.57. HRMS: Anal. Calc. for [M + H]⁺ C₃₅H₄₂N₇O₅: 640.3247;found: 640.3261 D-35 4N HCl in dioxane R₁ = R₂ =  

1.83 min (Cond.- D2); LCMS: Anal. Calc. for [M + H]⁺ C₃₅H₄₂N₇O₅: 640.32;found: 640.26. HRMS: Anal. Calc. for [M + H]⁺ C₃₅H₄₂N₇O₅: 640.3247;found: 640.3242 D-36 4N HCl in dioxane R₁ = R₂ =  

  stereochemical composition undetermined 1.87 min (Cond.- D2); LCMS:Anal. Calc. for [M + H]⁺ C₃₇H₄₆N₇O₅: 668.36; found: 668.29. HRMS: Anal.Calc. for [M + H]⁺ C₃₅H₄₆N₇O₅: 668.3560; found: 668.3530. D-37 4N HCl indioxane R₁ = R₂ =  

  stereochemical composition undetermined 2.26 min (Cond.- D2); LCMS:Anal. Calc. for [M + H]⁺ C₄₉H₅₄N₇O₅: 820.42; found: 820.31. HRMS: Anal.Calc. for [M + H]⁺ C₄₉H₅₄N₇O₅: 820.4186; found: 820.4174.

Examples D-38 to D-41

Examples D-38 to D-41 were prepared from their respective deprotectedanalogs [shown above, D-34, D-35, D-31 (see comment below), and D-36]and Cap-1 according to the procedure described for the preparation ofExample D-57. Purification of the final targets was accomplished using aShimadzu reverse phase preparative HPLC instrument (solvent systems:H₂O/MeOH/TFA or H₂O/ACN/TFA) and the final products were isolated as TFAsalts. Note: Example D-40 was prepared from D-31 and Cap-1 through itsrespective deprotected analog (which was not characterized and carriedforward directly) according to the procedure described for thepreparation of Example D-57. Purification of Example D-40 wasaccomplished using a Shimadzu reverse phase preparative HPLC instrument(solvent systems: H₂O/MeOH/TFA or H₂O/ACN/TFA) and the final product wasisolated as a TFA salt.

R_(t) (LC-Cond.); % Coupling homogeneity index; Example Protocol R₁ andR₂ MS data D-38 HATU, DIPEA, DMF R₁ = R₂ =  

2.21 min (Cond.- D2); LCMS: Anal. Calc. for [M + H]⁺ C₅₅H₆₄N₉O₇: 962.49;found: not obsd. HRMS: Anal. Calc. for [M + H]⁺ C₅₅H₆₄N₉O₇: 962.4929;found: 962.4929. D-39 HATU, DIPEA, DMF R₁ = R₂ =  

2.26 min (Cond.- D2); LCMS: Anal. Calc. for [M + H]⁺ C₅₅H₆₄N₉O₇: 962.49;found: 962.34. HRMS: Anal. Calc. for [M + H]⁺ C₅₅H₆₄N₉O₇: 962.4929;found: 962.4957. D-40 HATU, DIPEA, DMF R₁ = R₂ =  

  stereochemical composition undetermined 2.28 min (Cond.- D2); LCMS:Anal. Calc. for [M + H]⁺ C₅₇H₆₄N₉O₇: 986.49; found: 986.78. HRMS: Anal.Calc. for [M + H]⁺ C₅₇H₆₄N₉O₇: 986.4929; found: 986.4930. D-41 HATU,DIPEA, DMF R₁ = R₂ =  

  stereochemical composition undetermined 2.18 min (Cond.- D2); LCMS:Anal. Calc. for [M + H]⁺ C₅₇H₆₈N₉O₇: 990.52; found: 990.48. HRMS: Anal.Calc. for [M + H]⁺ C₅₇H₆₈N₉O₇: 990.5242; found: 990.5234.

Example OL-7

Example OL-7a

Prepared from 2,5-diphenyl imidazole according to the proceduredescribed for Example OL-1b. This afforded Example OL-7a (1.0 g, 71%yield) as a yellow solid. ¹H NMR (DMSO-d₆, 500 MHz) δ 13.07 (s, 1 H),8.25 (m, 4 H), 8.03 (s, 1 H), 7.73 (m, 4 H). LC/MS (Cond. OL2):R_(t)=1.34 min; Anal. Calc. for [M+H]⁺ C₁₅H₁₁N₄O₄: 311.07; found: 311.

Example OL-7b

Prepared from Example OL-7a according to the procedure described forExample OL-1c. This afforded Example OL-7b as an off-white solid (0.44g, 85% yield). ¹H NMR (DMSO-d₆, 500 MHz) δ 12.36 (bs, 1 H), 7.96 (bs, 1H), 7.54 (d, J=8.5 Hz, 4 H), 6.93 (d, J=8.5 Hz, 4 H), 5.49 (bs, 4 H).LC/MS (Cond. OL1): R_(t)=0.16 min; Anal. Calc. for [M+H]⁺ C₁₅H₁₅N₄:251.12; found: 251.

Example OL-7

Prepared from Example OL-7b and Carbobenzyloxy-L-Proline, according tothe procedure described for Example OL-1d. This afforded the TFA salt ofExample OL-7 (0.15 g, 67% yield) as an off-white solid. ¹H NMR (DMSO-d₆,500 MHz) δ 10.28 (s, 2 H), 9.26 (s, 1 H), 7.69 (m, 4 H), 7.42 (m, 4H),7.37 (m, 4 H), 7.32 (m, 1H), 7.21 (d, J=7.3 Hz, 2 H), 7.18 (m, 1 H),7.11 (m, 2 H), 5.09 (m, 3 H), 4.94 (d, J=13.2 Hz, 1 H), 4.39 (dd, J=8.4,3.9 Hz, 1 H), 4.35 (dd, J=8.4, 3.2 Hz, 1 H), 3.48 (m, 4 H), 2.25 (m, 2H), 1.89 (m, 6 H). LC/MS (Cond. OL1): R_(t)=1.54 min; Anal. Calc. for[M+H]⁺ C₄₁H₄₁N₆O₆: 713.30; found: 713.

Example OL-8

Prepared from Example OL-7b and L-Cbz-Alanine according to the proceduredescribed for Example OL-1d. This afforded the TFA salt of Example OL-8(0.13 g, 75% yield) as an off-white solid. ¹H NMR (DMSO-d₆, 500 MHz) δ10.21 (s, 2 H), 9.15 (s, 1 H), 7.69 (d, J=8.55 Hz, 4 H), 7.65 (d, J=7.02Hz, 2 H), 7.41 (d, J=8.55 Hz, 4 H), 7.36 (m, 6 H), 7.32 (m, 2 H), 7.25(bs, 1 H), 7.18 (bs, 1 H), 5.03 (m, 4 H), 4.19 (m, 2 H), 1.30 (d, J=7.02Hz, 6 H). LC/MS (Cond. OL3): R_(t)═R_(t)=1.52 min; Anal. Calc. for[M+H]⁺ C₃₇H₃₇N₆O₆: 661.27; found: 661.

Example OL-9

Prepared from Example OL-7b and (S)-2-(2-phenylacetamido)propanoic acidaccording to the procedure described for Example OL-1d. This affordedthe TFA salt of Example OL-9 (0.16 g, 78% yield) as an off-white solid.¹H NMR (DMSO-d₆, 500 MHz) δ 10.23 (s, 2 H), 9.17 (s, 1 H), 8.45 (d,J=7.02 Hz, 2 H), 7.67 (d, J=8.55 Hz, 4 H), 7.39 (d, J=8.55 Hz, 4 H),7.27 (m, 9 H), 7.21 (m, 3 H), 4.40 (m, 2 H), 3.49 (s, 4 H), 1.31 (d,J=7.02 Hz, 6H). LC/MS (Cond. OL3): R_(t)=1.42 min; Anal. Calc. for[M+H]⁺ C₃₇H₃₇N₆O₄: 629.28; found: 629.

Example OL-10

Prepared from Example OL-7b and(S)-1-(2-phenylacetyl)pyrrolidine-2-carboxylic acid according to theprocedure described for Example OL-1d. This afforded the TFA salt ofExample OL-10 (45 mg, 77% yield) as an off-white solid. ¹H NMR (DMSO-d₆,500 MHz) δ 10.22 and 10.41 (2s, 2 H), 9.26 (s, 1 H), 7.68 (d, J=8.85 Hz,4 H), 7.40 (m, 4 H), 7.30 (m, 4 H), 7.20 (m, 7 H), 4.44 and 4.66 (2dd,J=8.4, 3.8 Hz, 4 H), 3.70 (m, 4 H), 3.60 (m, 4 H), 2.16 (m, 2 H), 2.01(m, 2 H), 1.90 (m, 4 H). LC/MS (Cond. OL2): R_(t)=1.61 min; Anal. Calc.for [M+H]⁺ C₄₁H₄₁N₆O₄: 681.31; found: 681.

Example OL-11

Prepared from Example OL-7b and(2S,4R)-4-hydroxy-1-(2-phenylacetyl)pyrrolidine-2-carboxylic acidaccording to the procedure described for Example OL-1d. This affordedthe TFA salt of Example OL-11 (42 mg, 37% yield) as an off-white solid.¹H NMR (DMSO-d₆, 500 MHz) δ 10.25 and 10.41 (2s, 2 H), 9.13 (s, 1 H),7.65 (d, J=8.7 Hz, 4 H), 7.36 (d, J=8.7 Hz, 4 H), 7.24 (m, 10 H), 5.18(bs, 2 H), 4.48 (t, J=7.8 Hz, 2 H), 4.38 (m, 2 H), 3.65 (m, 6 H), 3.50(m, 4 H), 2.09 (m, 2 H), 1.95 (m, 2 H). LC/MS (Cond. OL1): R_(t)=1.31min; Anal. Calc. for [M+H]⁺ C₄₁H₄₁N₆O₆: 713.30; found: 713.

Example D-42

Example D-42a

4,5-Diphenyl-2-methylthiazole (5.0 g, 19.9 mmol) was added in twoportions to cold (0° C.), fuming nitric acid (50 mL). The mixture wasstirred at 0° C. for 1 h before it was allowed to warm to ambienttemperature where it stirred for 6 h. The mixture was then poured intocrushed ice/water and stirred for 1 h before the precipitate wassuction-filtered to afford Example D-42a (5.36 g, 79%) as a bright,yellow solid which was used directly in the next reaction. ¹H NMR(DMSO-d₆, 400 MHz) δ 8.25 (d, J=8.8 Hz, 2H), 8.21 (d, J=8.8 Hz, 2H),7.69 (d, J=8.8 Hz, 2H), 7.62 (d, J=8.8 Hz, 2H), 2.78 (s, 3H). LC/MS(Cond.-D1): R_(t)=2.31 min; Anal. Calc. for [M+H]⁺ C₁₆H₁₃N₃O₄S: 342.06;found: 342.05. HRMS: Anal. Calc. for [M+H]⁺ C₁₆H₁₃N₃O₄S: 342.0549;found: 342.0547.

Example D-42b

A suspension of 20% palladium hydroxide on carbon (0.20 g) in anhydrousmethanol (1 mL) was added to a solution of Example D-42a (0.50 g, 1.46mmol) in anhydrous methanol (20 mL). The mixture was subjected toballoon hydrogenation for 4 h at ambient temperature before it wassuction-filtered through Celite and concentrated in vacuo to affordExample D-42b (0.365 g, 89%) as a pale, yellow solid. ¹H NMR (MeOD-d₄,400 MHz) δ 7.15 (d, J=8.8 Hz, 2H), 6.97 (d, J=8.8 Hz, 2H), 6.61-6.58 (m,4H), 2.62 (s, 3H). LC/MS (Cond.-D1): R_(t)=0.85 min; Anal. Calc. for[M+H]⁺ C₁₆H₁₅N₃S: 282.11; found: 282.07. HRMS: Anal. Calc. for [M+H]⁺C₁₆H₁₅N₃S: 282.1065; found: 282.1056.

Example D-42

Example D-42 was prepared from Example D-42b and 1.0 eq. ofN—Ac-L-proline and 1.0 eq. of N-PhAc-L-proline according to theprocedure for Example OL-1d. This afforded D-42 (84.2 mg, 37%) as amixture of regioisomers as well as

Example D-43 (36.4 mg, 18%) and Example D-44 (43.9 mg, 17%) as colorlessoils (vide infra).

For Example D-42: ¹H NMR (MeOH-d₄, 400 MHz) δ 7.53-7.48 (m, 4 H),7.37-7.33 (m, 2 H), 7.28-7.19 (2m, 7 H), 4.60-4.46 (series of m, 2 H),3.75 (s, 2 H), 3.71-3.61 (2m, 4 H), 2.70 (s, 3 H), 2.30-2.23 (m, 2 H),2.09 and 1.96 (2s, 3 H), 2.08-1.92 (m, 6 H). LC/MS (Cond.-D1):R_(t)=2.10 min; Anal. Calc. for [M+H]⁺ C₃₆H₃₈N₅O₄S: 636.26; found:636.17. HRMS: Anal. Calc. for [M+H]⁺ C₃₆H₃₈N₅O₄S: 636.2645; found:636.2622.

Example D-43 and Example D-44

For Example D-43: ¹H NMR (MeOD-d₄, 400 MHz) δ 7.53-7.49 (m, 4H),7.38-7.33 (m, 2 H), 7.25-7.20 (m, 2 H), 4.55-4.45 (series of m, 2 H),3.72-3.66 (m, 2 H), 3.62-3.57 (m, 2 H), 2.70 (s, 3 H), 2.30-2.23 (m, 2H), 2.09 and 1.97 (2s, 6 H), 2.08-2.00 (m, 6 H). LC/MS (Cond.-D1):R_(t)=1.78 min; Anal. Calc. for [M+H]⁺ C₃₀H₃₄N₅O₄S: 560.23; found:560.15. HRMS: Anal. Calc. for [M+H]⁺ C₃₀H₃₄N₅O₄S: 560.2332; found:560.2334.

For Example D-44: ¹H NMR (MeOD-d₄, 400 MHz) δ 7.52-7.47 (m, 4 H),7.35-7.33 (m, 2 H), 7.28-7.18 (2m, 12 H), 4.60-4.50 (series of m, 2 H),3.75 (s, 4 H), 3.71-3.57 (series of m, 4 H), 2.70 (2s, 3 H), 2.25-2.20(m, 2 H), 2.10-1.95 (series of m, 6 H). LC/MS (Cond.-D1): R_(t)=2.34min; Anal. Calc. for [M+H]⁺ C₄₂H₄₂N₅O₄S: 712.30. found: 712.19. HRMS:Anal. Calc. for [M+H]⁺ C₄₂H₄₂N₅O₄S: 712.2958; found: 712.2951.

Example D-45

Example D-45a

p-Azidophenacyl bromide (1.0 g, 4.2 mmol) was added in one portion to astirred solution of p -aminobenzthioamide (0.64 g, 4.2 mmol) in absoluteethanol (10 mL). The mixture was heated to reflux for 2 h before it wascooled to ambient temperature, diluted with ether and chilled for 16 hat −20° C. before it was suction-filtered to afford Example D-45a (1.38g, 88%) as a mustard-colored solid. A portion of the residue was used tocharacterize the compound. The bulk of the material was taken up inethyl acetate and washed with saturated sodium bicarbonate solution andbrine, dried over Na₂SO₄ and concentrated. The free base was directlyused in the next step. ¹H NMR (MeOD-d₄, 500 MHz) δ 8.19 (d, J=8.6 Hz, 2H), 8.06 (d, J=8.9 Hz, 2 H), 7.88 (s, 1 H), 7.48 (d, J=8.8 Hz, 2 H),7.17 (d, J=8.9 Hz, 2 H); LC/MS (Cond.-D1): R_(t)=2.06 min; Anal. Calc.for [M+H]⁺ C₁₅H₁₂N₅S: 294.08. found: 294.10. HRMS: Anal. Calc. for[M+H]⁺ C₁₅H₁₂N₅S: 294.0814; found: 294.0812.

Example D-45b

Prepared from Example D-45a and N-acetyl-L-proline according to theprocedure described for Example OL-1d. There was isolated Example D-45a(440 mg mg, 82%) as a yellowish-tan solid. ¹H NMR (MeOD-d₄, 400 MHz) δ8.03-8.00 (m, 2 H), 7.98-7.95 (2m, 2 H), 7.74-7.68 (m, 3 H), 7.13-7.11(m, 2 H), 4.59-4.56 and 4.54-4.50 (2m, 1 H), 3.74-3.68 (m, 1 H),3.65-3.59 (m, 1 H), 2.31-2.25 (m, 1 H), 2.11 and 1.99 (2s, 3 H),2.09-1.96 (m, 3 H). LC/MS (Cond.-D1): R_(t)=2.50 min; Anal. Calc. for[M+H]⁺ C₂₂H₂₁N₆O₂S: 433.14; found: 433.15. HRMS: Anal. Calc. for [M+H]⁺C₂₂H₂₁N₆O₂S: 433.14467 found: 433.1464.

Example D-45c

Example D-45b (640.1 mg, 1.48 mmol) was hydrogenated at ambienttemperature under 1 atm of hydrogen for 2 h in methanol (20 mL) using20% palladium hydroxide on carbon (300 mg) to afford Example D-45c(586.1 mg, 97%) as an orange foam which was used directly. ¹H NMR(MeOD-d₄, 400 MHz) δ 10.41 and 10.22 (2s, 1H), 7.97-7.93 (m, 2H),7.77-7.68 (series of m, 5H), 6.63 (d, J=8.6 Hz, 1H), 5.37 (v br s, 2H),4.55-4.41 (2m, 1H), 3.64-3.50 (2m, 2H), 2.35-2.10 (2m, 1H), 2.01 and1.86 (2s, 3H), 1.96-1.87 (m, 3H). LC/MS (Cond.-D1): R_(t)=1.51 min;Anal. Calc. for [M+H]⁺ C₂₂H₂₃N₄O₂S: 407.15; found: 407.13. HRMS: Anal.Calc. for [M+H]⁺ C₂₂H₂₃N₄O₂S: 407.1542; found: 407.1539.

Example D-45

Prepared from Example D-45c and N-phenacetyl-L-proline according to theprocedure described for Example OL-1d. This afforded Example D-45 (17.9mg, 39%) as an off-white solid. ¹H NMR (DMSO-d₆, 400 MHz) δ 10.42,10.35, 10.23 and 10.13 (4s, 2H), 8.04-7.96 (m, 5H), 7.78-7.68 (m, 4H),7.33-7.19 (m, 5H), 4.69-4.41 (3m, 2H), 3.71 (s, 2H), 3.68-3.43 (seriesof m, 4H), 2.40-2.14 (2m, 2H), 2.01-1.86 (2s, 3H), 2.00-1.89 (m, 6H).LC/MS (Cond.-D1): R_(t)=2.26 min; Anal. Calc. for [M+H]⁺ C₃₅H₃₆N₅O₄S:622.25; found: 622.29. HRMS: Anal. Calc. for [M+H]⁺ C₃₅H₃₆N₅O₄S:622.2488; found: 622.2483.

Example D-46

Prepared from Example D-45c and5-oxo-1-(2-(thiophen-2-yl)ethyl)pyrrolidine-3-carboxylic acid accordingto the procedure described for Example OL-1d. This afforded Example D-46(14.3 mg, 31%) as an off-white solid. ¹H NMR (DMSO-d₆, 400 MHz) δ 10.43and 10.24 (2s, 2 H), 8.02-7.96 (m, 5 H), 7.79-7.69 (m, 4 H), 7.36-7.34(m, 1 H), 6.96-6.92 (m, 2 H), 4.55-4.53 and 4.44-4.41 (2m, 1 H),3.63-3.55 (m, 2 H), 3.50-3.43 (m, 4 H), 3.03-3.00 (m, 2 H), 2.53 (s, 1H), 2.40-2.10 (2 m, 1 H), 2.01-1.86 (2s, 3 H), 1.94-1.90 (m, 3 H). LC/MS(Cond.-D1): R_(t)=2.29 min; Anal. Calc. for [M+H]⁺ C₃₃H₃₄N₅O₄S₂: 628.21;found: 628.13. HRMS: Anal. Calc. for [M+H]⁺ C₃₃H₃₄N₅O₄S₂: 628.2052;found: 628.2076.

Example D-47

Example D-47a

Prepared from Example D-45c and(S)-1-(tert-butoxycarbonyl)-2,5-dihydro-1H-pyrrole-2-carboxylic acidaccording to the procedure described for Example OL-1d. This affordedExample D-47a (554 mg, 76%) as a pale, yellow solid. ¹H NMR (DMSO-d₆,500 MHz) δ 10.41, 10.22 and 10.20 (3s, 2 H), 8.01-7.96 (m, 5 H),7.78-7.70 (m, 4 H), 6.08-6.04 (m, 1 H), 5.88-5.85 (m, H), 5.02-4.97 (m,1 H), 4.55-4.41 (2m, 1 H), 4.23-4.14 (m, 1 H), 4.10-4.06 (m, 1 H),3.63-3.59 (m, 1 H), 3.56-3.51 (m, 1 H), 2.18-2.14 (m, 1 H), 2.01 and1.86 (2s, 3 H), 1.99-1.91 (m, 3 H), 1.43 and 1.31 (2s, 9 H). LC/MS(Cond.-D1): R_(t)=2.27 min; Anal. Calc. for [M+H]⁺ C₃₂H₃₆N₅O₅S: 602.24.found: 602.28. HRMS: Anal. Calc. for [M+H]⁺ C₃₂H₃₆N₅O₅S: 602.2437;found: 602.2458.

Example D-47b

Example D-47a (0.50 g, 0.828 mmol) was subjected to acidic hydrolysiswith 4N HCl in dioxane (20 mL) for 3 h before it was concentrated downin vacuo to yield Example D-47b (0.50 g, 113+%) as a yellow solid whichwas used directly. ¹H NMR (MeOH-d₄, 400 MHz) δ 7.99-7.93 (m, 4H),7.73-7.65 (m, 5H), 6.13-6.09 (m, 2H), 5.22-5.21 (m, 1H), 4.60-4.50 (2m,1H), 4.30-4.25 (m, 1H), 4.18-4.14 (m, 1H), 3.73-3.68 (m, 1H), 3.65-3.59(m, 1H), 2.50-2.25 (2m, 1H), 2.11 and 1.99 (2s, 3H), 2.09-2.00 (m, 3H).LC/MS (Cond.-D1): R_(t)=1.72 min; Anal. Calc. for [M+H]⁺ C₂₂H₂₈N₅O₃S:502.19; found: 502.15 HRMS: Anal. Calc. for [M+H]⁺ C₂₂H₂₈N₅O₃S:502.1913; found: 502.1918.

Example D-47

Prepared from Example D-47b and thiophene-2-carboxylic acid according tothe procedure described for Example D-57. This afforded Example D-47(15.1 mg, 27%) as an off-white solid. ¹H NMR (DMSO-d₄, 400 MHz) δ 10.42,10.34 and 10.23 (3s, 2H), 8.03-7.97 (m, 5H), 7.87-7.86 (m, 1H),7.77-7.70 (m, 5H), 7.24-7.22 (m, 1H), 6.20-6.18 (m, 1H), 6.03-6.01 (m,1H), 5.70-5.40 (2m, 1H), 4.80-4.75 (m, 1H), 4.69-4.65 (m, 1H), 4.55-4.41(2m, 1H), 3.63-3.50 (2m, 2H), 2.31-2.13 (2m, 1H), 2.01 and 1.86 (2s,3H), 1.99-1.87 (m, 3H). LC/MS (Cond.-D1): R_(t)=2.11 min; Anal. Calc.for [M+H]⁺ C₃₂H₃₀N₅O₄S₂: 612.17; found: 612.12. HRMS: Anal. Calc. for[M+H]⁺ C₃₂H₃₀N₅O₄S₂: 612.1739; found: 612.1716.

Example D-48

Prepared from Example D-47b and 2-(thiophen-2-yl)acetic acid accordingto the procedure described for Example D-57. This afforded Example D-48(23.9 mg, 41%) as a light, yellow solid. ¹H NMR (DMSO-d₆, 400 MHz) δ10.46, 10.42, 10.24 and 10.23 (4s, 2H), 8.05-7.94 (m, 5H), 7.78-7.68(2m, 4H), 7.40-7.36 (2m, 1H), 6.99-6.89 (series of m, 2H), 6.14-6.12 (m,1H), 6.03-5.92 (2m, 1H), 5.43-5.41 and 5.17-5.16 (2m, 1H), 4.55-4.42 (m,1H), 4.46 (s, 2H), 4.00-3.98 (m, 1H), 3.64-3.51 (m, 2H), 2.36-2.10 (2m,2H), 2.01 and 1.86 (2s, 3H), 1.97-1.90 (m, 3H). LC/MS (Cond.-D1):R_(t)=2.17 min; Anal. Calc. for [M+H]⁺ C₃₃H₃₂N₅O₄S₂: 626.19; found:626.12. HRMS: Anal. Calc. for [M+H]⁺ C₃₃H₃₂N₅O₄S₂: 626.1896; found:626.1891.

Example D-49

Prepared from Example D-47b and 2-phenylacetic acid according to theprocedure described for Example D-57. This afforded Example D-49 (24.0mg, 42%) as an off-white solid. ¹H NMR (DMSO-d₆, 400 MHz) δ 10.46,10.42, 10.24 and 10.23 (4s, 2H), 8.05-7.96 (m, 5H), 7.79-7.68 (2m, 4H),7.34-7.19 (m, 5H), 6.14-6.10 (m, 1H), 6.02-5.92 (2m, 1H), 5.41-5.39 and5.16-5.15 (2m, 1H), 4.55-4.52 and 4.44-4.41 (2m, 2H), 3.74 (s, 2H),3.64-3.51 (2m, 3H), 2.36-2.30 and 2.20-2.10 (2m, 1H), 2.01 and 1.86 (2s,3H), 1.95-1.90 (m, 3H). LC/MS (Cond.-D1): R_(t)=2.21 min; Anal. Calc.for [M+H]⁺ C₃₅H₃₄N₅O₄S: 620.23; found: 620.17. HRMS: Anal. Calc. for[M+H]⁺ C₃₅H₃₄N₅O₄S: 620.2332; found: 620.2355.

Example D-50

Prepared from Example D-47b and isoxazole-5-carboxylic acid according tothe procedure described for Example D-57. This afforded Example D-50(21.4 mg, 39%) as an off-white solid. ¹H NMR (DMSO-d₆, 400 MHz) δ 10.48,10.42, 10.39 and 10.23 (4s, 2H), 8.83 and 8.69 (2m, 1H), 8.03-7.95 (m,5H), 7.78-7.56 (series of m, 4H), 7.20-7.19 and 7.04-7.03 (2m, 1H),6.20-6.18 (m, 1H), 6.07-6.02 (m, 1H), 5.80-5.76 and 5.41-5.39 (2m, 1H),4.78-4.41 (series of m, 3H), 3.63-3.50 (2m, 2H), 2.35-2.13 (2m, 1H),2.01 and 1.86 (2s, 3H), 1.99-1.87 (m, 3H). LC/MS (Cond.-D1): R_(t)=1.98min; Anal. Calc. for [M+H]⁺ C₃₁H₂₉N₆O₅S: 597.19; found: 597.13. HRMS:Anal. Calc. for [M+H]⁺ C₃₁H₂₉N₆O₅S: 597.1920; found: 597.1936.

Example D-51

Prepared from Example D-47b and (R)-tetrahydrofuran-2-carboxylic acidaccording to the procedure described for Example D-57. This affordedExample D-51 (27.1 mg, 49%) as an off-white solid. ¹H NMR (DMSO-d₆, 400MHz) δ 10.42, 10.39 and 10.24 (3s, 2H), 8.03-7.97 (m, 5H), 7.79-7.74 (m,2H), 7.70-7.68 (m, 2H), 6.12-6.10 (m, 1H), 5.99-5.91 (2m, 1H), 5.53-5.51and 5.15-5.14 (2m, 1H), 4.62-4.20 (series of m, 4H), 3.85-3.70 (m, 2H),3.64-3.51 (2m, 2H), 2.35-2.05 (2m, 2H), 2.01 and 1.86 (2s, 3H),2.00-1.83 (m, 6H). LC/MS (Cond.-D1): R_(t)=1.99 min; Anal. Calc. for[M+H]⁺ C₃₂H₃₄N₅O₅S: 600.23; found: 600.17. HRMS: Anal. Calc. for [M+H]⁺C₃₂H₃₄N₅O₅S: 600.2281; found: 600.2286.

Example D-52

Prepared from Example D-47b and (S)-tetrahydrofuran-2-carboxylic acidaccording to the procedure described for Example D-57. This affordedExample D-52 (12.4 mg, 22%) as an off-white solid. ¹H NMR (DMSO-d₆, 400MHz) δ 10.42, 10.25 and 10.24 (3s, 2 H), 8.02-7.96 (m, 5 H), 7.79-7.74(m, 2 H), 7.71-7.69 (m, 2 H), 6.12-6.10 (m, 1 H), 5.96-5.92 (m, 1 H),5.42-5.40 and 5.17-5.15 (2m, 1 H), 4.66-4.64 (m, 1 H), 4.58-4.36 (seriesof m, 3 H), 3.83-3.76 (m, 2 H), 3.66-3.50 (2m, 2 H), 2.35-2.05 (2m, 2H), 2.01 and 1.86 (2s, 3 H), 1.96-1.83 (m, 6 H). LC/MS (Cond.-D1):R_(t)=2.01 min; Anal. Calc. for [M+H]⁺ C₃₂H₃₄N₅O₅S: 600.23; found:600.15. HRMS: Anal. Calc. for [M+H]⁺ C₃₂H₃₄N₅O₅S: 600.2281; found:600.2305.

Example D-53

Prepared from Example D-47b and benzoic acid according to the proceduredescribed for Example D-57. This afforded Example D-53 (16.8 mg, 30%) asa light, yellow solid. ¹H NMR (DMSO-d₆, 400 MHz) δ 10.42, 10.33, 10.23and 9.96 (4s, 2 H), 8.03-7.90 (m, 5 H), 7.79-7.73 (m, 4 H), 7.63-7.61(m, 1 H), 7.51-7.48 (m, 2 H), 7.43-7.34 (2m, 2 H), 6.18-5.88 (series ofm, 2 H), 5.42-5.40 and 5.22 (2 m, 1 H), 4.55-4.41 (series of m, 2 H),4.21-4.14 (m, 1 H), 3.64-3.50 (2m, 2 H), 2.35-2.15 (2m, 1 H), 2.01 and1.86 (2s, 3 H), 1.96-1.88 (m, 3 H). LC/MS (Cond.-D1): R_(t)=2.12 min;Anal. Calc. for [M+H]⁺ C₃₄H₃₂N₅O₄S: 606.22. found: 606.15. HRMS: Anal.Calc. for [M+H]⁺ C₃₄H₃₂N₅O₄S: 606.2175; found: 606.2188.

Example OL-12

Example OL-12a

p-Nitroaniline (1.5 g, 10.86 mmol) and p-nitrobenzoyl chloride (2.05 g,11.08 mmol) were mixed in tetrahydrofuran (30 mL) and stirred at ambienttemperature overnight. A brown solid crashed out, which was filtered andwashed with tetrahydrofuran to give Example OL-12a (2.40 g, 77% yield)which was used without further purification. ¹H NMR (DMSO-d₆, 500 MHz) δ11.10 (s, 1 H), 8.40 (d, J=9.1, 2 H), 8.30 (d, J=9.1 Hz, 2 H), 8.21 (d,J=9.1 Hz, 2 H), 8.06 (d, J=9.1 Hz, 2 H). LC/MS (Cond. OL1): R_(t)=1.57min; Anal. Calc. for [M+H]⁺ C₁₃H₁₀N₃O₅: 288.05; found: 288.

Example OL-12b

Phosphorous pentachloride (0.32 g, 1.53 mmol) was added to a solution ofExample OL-12a (0.4 g, 1.39 mmol) in benzene (15 mL). The mixture washeated to reflux temperature for 4 h, concentrated under reducedpressure and the residue was taken up in tetrahydrofuran (5 mL). Thesolution was then transferred via-canula into a solution of hydrazine(0.44 mL, 13.9 mmol) in tetrahydrofuran (10 mL) at 0° C. The mixture wasstirred at ambient temperature for 1 h, poured into water and extractedwith ethyl acetate (2×). The combined organic layers were washed withbrine, dried (Na₂SO₄), filtered and concentrated under reduced pressureto give Example OL-12b (0.38 g, 92% yield) as a yellow solid which wasused without further purification. ¹H NMR (DMSO-d₆, 500 MHz) δ 8.85 (bs,1 H), 8.19 (d, J=9.1, 2 H), 8.07 (d, J=9.1 Hz, 2 H), 7.73 (d, J=9.1 Hz,2 H), 7.35 (bs, 2 H), 6.59 (d, J=9.1 Hz, 2 H). LC/MS (Cond. OL2):R_(t)=1.05 min; Anal. Calc. for [M+H]⁺ C₁₃H₁₂N₅O₄: 302.08; found: 302.

Example OL-12c

Carbonyldiimidazole (0.1 g, 0.65 mmol) was added to a solution ofExample OL-12b (0.16 g, 0.54 mmol) in tetrahydrofuran (5 mL), andallowed to stir at ambient temperature until the disappearance of thestarting material, as judged by TLC. The mixture was then concentratedunder reduced pressure, and the residue was re-dissolved in ethylacetate, washed with 0.1 N HCl, water and brine, dried (MgSO₄), filteredand concentrated. The remaining residue was purified by flashchromatography, eluting with ethyl acetate/hexanes (50:50) and theobtained oil was dissolved in dichloromethane and triturated withhexanes, to give Example OL-12c (0.11 g, 62% yield) as a yellowishsolid. ¹H NMR (DMSO-d₆, 500 MHz) δ 12.81 (bs, 1 H), 8.33 (d, J=8.8, 2H), 8.22 (d, J=8.8 Hz, 2 H), 7.59 (d, J=8.8 Hz, 2 H), 7.57 (d, J=8.8 Hz,2 H). LC/MS (Cond. OL2): R_(t)=1.34 min; Anal. Calc. for [M+H]⁺C₁₄H₁₀N₅O₅: 328.06. found: 328.

Example OL-12d

Prepared from Example OL-12c according to the procedure described forExample OL-1c. This afforded Example OL-12d (73 mg, 63% yield) as anoff-white solid. ¹H NMR (DMSO-d₆, 500 MHz) δ 11.65 (s, 1 H), 6.95 (d,J=8.5, 2 H), 6.82 (d, J=8.5 Hz, 2 H), 6.56 (d, J=8.5 Hz, 2 H), 6.42 (d,J=8.5 Hz, 2H), 5.43 (bs, 2 H), 5.34 (bs, 2 H). LC/MS (Cond. OL1):R_(t)=0.21 min; Anal. Calc. for [M+H]⁺ C₁₄H₁₄N₅O: 268.11; found: 268.

Example OL-12

Prepared from Example OL-12d and L-Cbz-Alanine, according to theprocedure described for Example OL-1d. This afforded Example OL-12 (60mg, 65% yield) as an off-white solid. ¹H NMR (DMSO-d₆, 500 MHz) δ 12.01(s, 1 H), 10.14 (d, J=12.8, 2 H), 7.62 (m, 4 H), 7.54 (d, J=8.7 Hz, 2H), 7.31 (m, 10 H), 7.18 (dd, J=11.9, 8.9 Hz, 4 H), 5.00 (m, 4 H), 4.15(m, 2 H), 1.28 (d, J=7.3 Hz, 3 H), 1.24 (d, J=7.3 Hz, 3 H). LC/MS (Cond.OL2): R_(t)=1.85 min; Anal. Calc. for [M+H]⁺ C₃₆H₃₆N₇O₇: 678.26; found:678.

Example OL-13

Prepared from Example OL-12d and Carbobenzyloxy-L-Proline, according tothe procedure described for Example OL-1d. This afforded Example OL-13(71 mg, 72% yield). ¹H NMR (DMSO-d₆, 500 MHz) δ 12.07 (s, 1 H), 10.23(d, J=3.66 Hz, 1 H), 10.19 (d, J=5.12 Hz, 1 H), 7.66 (m, 2 H), 7.54 (m,2 H), 7.35 (m, 4 H), 7.21 (m, 8 H), 7.09 (d, J=7.3 Hz, 1 H), 7.04 (d,J=6.9 Hz, 1 H), 5.07 (m, 3 H), 4.90 (m, 1 H), 4.35 (m, 2 H), 3.47 (m, 4H), 2.22 (m, 2 H), 1.89 (m, 6 H). LC/MS (Cond. OL2): R_(t)=1.68 min;Anal. Calc. for [M+H]⁺ C₄₀H₄₀N₇O₇: 730.29; found: 730.

Example OL-14

Example OL-14a

p-Toluenesulfonic acid (25 mg, catalytic) was added to a mixture of4-Nitro phenyl-N-(4-nitro-phenyl)-hydrazonamide (160 mg, 053 mmol) andN,N′-dimethylformamide dimethylacetal (92 μL, 069 mmol) in benzene (10mL). The suspension was stirred at reflux temperature under Dean-Starkconditions with a yellow solid forming after 1 h. The solvent wasremoved under reduced pressure and the residue was taken up in ethylacetate, washed with 0.1 N HCl and brine, dried (MgSO₄), filtered andconcentrated. The residue was purified by flash chromatography, elutingwith dichloromethane and methanol/dichloromethane (10:90), to giveExample OL-14a (0.11 g, 67% yield) as a yellow solid. ¹H NMR (DMSO-d₆,500 MHz) δ 9.11 (s, 1 H), 8.37 (d, J=8.8, 2 H), 8.26 (d, J=8.8 Hz, 2 H),7.72 (d, J=8.8 Hz, 2 H), 7.69 (d, J=8.8 Hz, 2 H). LC/MS (Cond. OL2):R_(t)=1.20 min; Anal. Calc. for [M+Na]⁺ C₁₄H₉N₅NaO₄: 334.06; found: 334.

Example OL-14b

Prepared from Example OL-14a according to the procedure described forExample OL-1c. This afforded Example OL-14b (60 mg, 75% yield) as anoff-white solid. ¹H NMR (DMSO-d₆, 500 MHz) δ 8.49 (s, 1 H), 7.07 (d,J=8.5, 2 H), 6.94 (d, J=8.8 Hz, 2 H), 6.59 (d, J=8.8 Hz, 2 H), 6.47 (d,J=8.5 Hz, 2 H), 5.46 (s, 2 H), 5.43 (s, 2 H). LC/MS (Cond. OL2):R_(t)=0.18 min; Anal. Calc. for [M+H]⁺ C₁₄H₁₄N₅: 252.12; found: 252.

Example OL-14

Prepared from Example OL-14b and Carbobenzyloxy-L-Proline according tothe procedure described for Example OL-1d. This afforded the TFA salt ofExample OL-14 (46 mg, 75% yield) as an off-white solid. ¹H NMR (DMSO-d₆,500 MHz) δ 10.31 (m, 1 H), 10.22 (d, J=7.2 Hz, 1 H), 8.82 d, J=3.0 Hz, 1H), 7.70 (m, 2 H), 7.60 (m, 2 H), 7.32 (t, J=4.3 Hz, 4 H), 7.31 (m, 4H), 7.18 (m, 3 H), 7.10 (d, J=7.3 Hz, 1 H), 7.05 (t, J=7.0 Hz, 1 H),5.08 (m, 3 H), 4.92 (m, 1 H), 4.35 (m, 2 H), 3.45 (m, 5 H), 2.34 (m, 2H), 1.88 (m, 6 H). LC/MS (Cond. OL1): R_(t)=1.56 min; Anal. Calc. for[M+H]⁺ C₄₀H₄₀N₇O₆: 714.30; found: 714.

Example OL-15

-   Prepared from Example OL-14b and    (S)-1-(2-phenylacetyl)pyrrolidine-2-carboxylic acid according to the    procedure described for Example OL-1d. This afforded the TFA salt of    Example OL-15 (46 mg, 63% yield) as an off-white solid. ¹H NMR    (DMSO-d₆, 500 MHz) δ 10.25 and 10.43 (2s, 1 H), 10.17 and 10.35 (2s,    1 H), 8.82 (s, 1 H), 7.69 (d, J=8.8 Hz, H), 7.59 (d, J=8.8 Hz, 2 H),    7.24 (m, 14 H), 4.42 (m, 2 H), 3.69 (d, J=4.4 Hz, 4 H), 3.59 (m, 4    H), 3.40 (m, 1 H), 2.14 (m, 2 H), 1.95 (m, 6 H). LC/MS (Cond. OL1):    R_(t)=1.50 min; Anal. Calc. for [M+H]⁺ C₄₀H₄₀N₇O₄: 682.31; found:    682.

Example OL-16

Prepared from Example OL-14b and L-Cbz-Alanine according to theprocedure described for Example OL-1d. This afforded the TFA salt ofExample OL-16 (40 mg, 45% yield) as an off-white solid. ¹H NMR (DMSO-d₆,500 MHz) δ 10.68 (s, 1 H), 10.59 (s, 1 H), 9.22 (d, J=2.1, 1 H), 8.15(d, J=8.5, 2 H), 8.08 (m, 1 H), 8.04 (d, J=8.8 Hz, 2 H), 7.76 (m, 13 H),7.64 (m, 1 H), 7.53 (m, 1 H), 5.45 (m, 4 H), 4.62 (m, 2 H), 1.73 (d,J=7.3 Hz, 3 H), 1.71 (d, J=7.3 Hz, 3 H). LC/MS (Cond. OL2): R_(t)=1.65min; Anal. Calc. for [M+H]⁺ C₃₆H₃₆N₇O₆: 662.26; found: 662.

Example OL-17

Prepared from Example OL-14b and(2S,4R)-4-hydroxy-1-(2-phenylacetyl)pyrrolidine-2-carboxylic acidaccording to the procedure described for Example OL-1d. This affordedthe TFA salt of Example OL-17 (52 mg, 52% yield) as an off-white solid.¹H NMR (DMSO-d₆, 500 MHz) δ 10.28 and 10.47 (2s, 1 H), 10.19 and 10.39(2s, 1 H), 8.77 (s, 1 H), 7.69 (d, J=8.5 Hz, 2 H), 7.58 (d, J=8.5 Hz, 2H), 7.25 (m, 14 H), 5.14 (bs, 2 H), 4.48 (q, J=7.8 Hz, 2 H), 4.38 (m, 2H), 3.67 (m, 6 H), 3.49 (m, 4 H), 2.10 (m, 2 H), 1.95 (m, 2 H). LC/MS(Cond. OL2): R_(t)=1.37 min; Anal. Calc. for [M+H]⁺ C₄₀H₄₀N₇O₆: 714.30;found: 714.

Example MS-8

Prepared from commercially available4,4′-(1,3,4-oxadiazole-2,5-diyl)dianiline and(S)-1-(benzyloxycarbonyl)pyrrolidine-2-carboxylic acid (i.e.N-CBz-L-proline) according to the procedure described for Example OL-1d.This afforded Example MS-8 (16.1 mg, 11%) as a colorless film. ¹H NMR(CDCl₃, 500 MHz) δ 9.67 (br s, 2 H), 8.02 (m, 2 H), 7.81 (m, 4 H), 7.55(m, 4 H), 7.20-7.36 (series of m, 8 H), 5.16-5.25 (m, 4 H), 4.50 (br s,2 H), 3.63 (br s, 2 H), 3.52 (br s, 2 H), 2.32 (m, 2 H), 1.97-2.12 (m, 6H). LC/MS (Cond.-MS-W1): R_(t)=1.82 min; Anal. Calc. for [M+H]⁺C₄₀H₃₉N₆O₇: 715.28; found: 715.41.

Example MS-9

Prepared from commercially available4,4′-(1,3,4-oxadiazole-2,5-diyl)dianiline and(S)-1-(2-phenylacetyl)pyrrolidine-2-carboxylic acid (i.e.N-phenacetyl-L-proline) according to the procedure described for ExampleOL-1d. This afforded Example MS-9 (22.7 mg, 17%) as a colorless film. ¹HNMR (CDCl₃, 500 MHz) δ 9.91 (s, 2 H), 7.72-7.70 (m, 4 H), 7.50-7.48 (m,4 H), 7.33-7.25 (m, 10 H), 4.84 (br s, 4 H), 4.63 (s, 2 H), 3.77 (s, 2H), 3.61-3.59 (m, 2 H), 2.24-2.23 (m, 4 H), 1.98 (br s, 4 H); LC/MS(Cond. MS-W1): R_(t)=1.78 min; Anal. Calc. for [M+H]⁺ C₄₀H₃₉N₆O₅:683.30; found: 683.44.

Example D-54, Example D-55, and Example D-56

Examples D-54, D-55 and D-56 were prepared from commercially available4,4′-(1,3,4-oxadiazole-2,5-diyl)dianiline and 1.0 eq. of phenylaceticacid and 1.0 eq. acetic acid according to the procedure described forExample OL-1d. There was isolated a statistical mixture of products(Example D-54, Example D-55 and Example D-56) which were purified bypreparative HPLC on a C18-reverse phase column (MeOH/H₂O/TFA) to giveall three components separately.

For Example D-54 (84.2 mg, 35%), off-white solid. ¹H NMR (MeOH-d₄, 400MHz) δ 7.90-7.80 and 7.71-7.68 (2m, 4H), 7.68-7.62 and 7.57-7.54 (2m,4H), 7.28-7.27 (m, 3H), 7.22-7.16 (m, 2H), 4.54-4.51 (m, 2H), 3.77 (2s,2H), 3.75-3.56 (m, 4H), 2.40-2.30 and 2.22-2.06 (m, 2H), 2.13 and 1.97(2s, 3H), 2.00-1.90 (m, 6H). LC/MS (Cond.-D1): R_(t)=2.18 min; Anal.Calc. for [M+H]⁺ C₃₄H₃₅N₆O₅: 607.26. found: 607.23. HRMS: Anal. Calc.for [M+H]⁺ C₃₄H₃₅N₆O₅: 607.2669; found: 607.2669.

For Example D-55 (36.4 mg, 17%), off-white solid. ¹H NMR (MeOH-d₄, 400MHz) δ 7.98-7.94 and 7.85-7.83 (2m, 4H), 7.78-7.72 and 7.67-7.65 (2m,4H), 4.60-4.53 (m, 2H), 3.75-3.68 (m, 2H), 3.65-3.60 (m, 2H), 2.50-2.40and 2.32-2.23 (2m, 2H), 2.13, 2.12 and 1.99 (3s, 6H), 2.10-1.97 (m, 6H).LC/MS (Cond.-D1): R_(t)=1.79 min; Anal. Calc. for [M+H]⁺ C₂₈H₃₀N₆O₅:531.24. found: 531.37. HRMS: Anal. Calc. for [M+H]⁺ C₂₈H₃₀N₆O₅:531.2356; found: 531.2338.

For Example D-56 (43.9 mg, 16%), off-white solid. ¹H NMR (MeOH-d₄, 400MHz) δ 7.97-7.92 and 7.74-7.72 (2m, 4H), 7.72-7.68 and 7.58-7.56 (2m,4H), 7.29-7.28 (m, 6H), 7.24-7.19 (m, 4H), 4.52-4.49 (m, 2H), 3.80 and3.79 (2s, 4H), 3.76-3.72 (m, 2H), 3.67-3.64 (m, 2H), 2.15-2.05 (m, 4H),1.98-1.90 (m, 4H). LC/MS (Cond.-D1): R_(t)=2.42 min; Anal. Calc. for[M+H]⁺ C₄₀H₃₉N₆O₅: 683.30. found: 683.26. HRMS: Anal. Calc. for [M+H]⁺C₄₀H₃₉N₆O₅: 683.2982; found: 683.2993. Note: Example MS-9 is the same asExample D-56, however, these were prepared differently.

Example D-57

Example D-57a

Prepared from commercially available4,4′-(1,3,4-oxadiazole-2,5-diyl)dianiline and(S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid according tothe procedure described for Example OL-1d. This afforded Example D-57a(2.85 g, 89%) as a white solid. ¹H NMR (DMSO-d₆, 400 MHz) δ 10.38 and10.37 (2s, 2H), 8.08 (d, J=8.8 Hz, 4H), 7.87-7.84 (m, 4H), 4.31 and 4.22(2m, 2H), 3.47-3.41 (m, 2H), 3.39-3.35 (m, 2H), 2.24-2.18 (m, 2H),1.94-1.81 (2m, 6H), 1.41 and 1.27 (2s, 18H); LC/MS (Cond. D1):R_(t)=2.42 min; Anal. Calc. for [M+H]⁺ C₃₄H₄₃N₆O₇: 647.32; found:647.28. HRMS: Anal. Calc. for [M−H]⁻ C₃₄H₄₁N₆O₇: 645.3037; found:645.3016.

Example D-57b

A cold (0° C.) solution of 4N HCl in dioxane (20 mL) was added toExample D-57a (2.50 g, 3.86 mmol). The mixture was stirred rapidly at 0°C. for 1 h before it was allowed to warm up to room temperature. After 1h at room temperature, the mixture was concentrated down in vacuo toafford Example D-57b (1.74 g, 86%) as a white solid. ¹H NMR (DMSO-d₆,400 MHz) δ 11.38 (s, 2H), 10.01-10.00 (m, 2H), 8.74-8.72 (m, 2H), 8.12(d, J=8.8 Hz, 4H), 7.91 (d, J=8.8 Hz, 4H), 4.49-4.46 (m, 2H), 3.31-3.25(m, 4H), 2.49-2.43 (m, 2H), 2.03-1.92 (m, 6H); LC/MS (Cond.-D1):R_(t)=1.27 min; Anal. Calc. for [M+H]⁺ C₂₄H₂₉N₆O₃: 447.21. found:447.22. HRMS: Anal. Calc. for [M+H]⁺ C₂₄H₂₉N₆O₃: 447.2145; found:447.2120.

Example D-57

HATU (10.3 mg, 0.103 mmol) was added in one portion to a stirredsolution of Example D-57b (42 mg, 0.094 mmol), diisopropylethylamine (97mg, 0.753 mmol) and 2-cyclopropylacetic acid (10.4 mg, 0.103 mmol; 1.0eq. of each acid was used for the unsymmetrical cases) in anhydrousdimethylformamide (1 mL) at ambient temperature. The mixture was stirredfor 4 h before it was diluted with methanol (1 mL) and purified bypreparatory HPLC on C₁₈— reverse phase to afford Example D-57 as atrifluoroacetic acid salt. The salt was taken up in methanol (2.0 mL)and free-based using a UCT CHQAX12M6 anion exchange cartridge to affordExample D-57 (35.8 mg, 61%, free base) as an off-white solid. ¹H NMR(MeOH-d₄, 400 MHz) δ 7.99-7.94 and 7.79-7.77 (2m, 4H), 7.77-7.72 and7.65-7.63 (2m, 4H), 4.61-4.57 (m, 2H), 3.71-3.58 (2m, 4H), 2.42-233 (m,4H), 2.29-1.95 (3m, 8H), 1.09-1.02 (m, 2H), 0.55-0.47 (m, 4H), 0.23-0.15(m, 4H). LC/MS (Cond.-D1): R_(t)=2.26 min; Anal. Calc. for [M+H]⁺C₃₄H₃₉N₆O₅: 611.30. found: 611.25. HRMS: Anal. Calc. for [M+H]⁺C₃₄H₃₉N₆O₅: 611.2982; found: 611.2971.

Example D-58

Prepared from Example D-57b and cyclopropanecarboxylic acid according tothe procedure described for Example D-57. This afforded Example D-58(34.0 mg, 61%) as an off-white solid. ¹H NMR (DMSO-d₆, 400 MHz) δ 10.50and 10.39 (2s, 2H), 8.10-8.05 (m, 4H), 7.87-7.82 (m, 4H), 4.78-4.75 and4.47-4.43 (2m, 2H), 3.82-3.70 (2m, 4H), 2.25-1.80 (series of m, 10H),0.77-0.64 (m, 8H). LC/MS (Cond.-D1): R_(t)=2.06 min; Anal. Calc. for[M+H]⁺ C₃₂H₃₅N₆O₅: 583.27; found: 583.38. HRMS: Anal. Calc. for [M+H]⁺C₃₂H₃₅N₆O₅: 583.2669; found: 583.2656.

Example D-59

Prepared from Example D-57b and cyclobutanecarboxylic acid according tothe procedure described for Example D-57. This afforded Example D-59(21.0 mg, 36%) as an off-white solid. ¹H NMR (MeOH-d₄, 400 MHz) δ8.05-8.00 and 7.89-7.87 (2m, 4H), 7.81-7.76 and 7.71-7.69 (2m, 4H),4.56-4.53 (m, 2H), 3.65-3.51 (2m, 4H), 3.46-3.39 (m, 2H), 2.35-1.94(series of m, 18H), 1.90-1.80 (m, 2H). LC/MS (Cond.-D1): R_(t)=2.33 min;Anal. Calc. for [M+H]⁺ C₃₄H₃₉N₆O₅: 611.30; found: 611.40. HRMS: Anal.Calc. for [M+H]⁺ C₃₄H₃₉N₆O₅: 611.2982; found: 611.2997.

Example D-60

Prepared from Example D-57b and (S)-tetrahydrofuran-2-carboxylic acidaccording to the procedure described for Example D-57. This affordedExample D-60 (35.2 mg, 57%) as an off-white solid. ¹H NMR (MeOH-d₄, 400MHz) δ 7.97-7.93 and 7.80-7.78 (2m, 4 H), 7.74-7.71 and 7.64-7.61 (2m, 4H), 4.72-4.66 (m, 2 H), 4.59-4.55 and 4.48-4.43 (2m, 2 H), 3.97-3.92 (m,2 H), 3.88-3.82 (m, 2 H), 3.79-3.72 (m, 2 H), 3.69-3.62 (m, 2 H),2.33-2.21 (m, 4 H), 2.18-2.08 (m, 4 H), 2.05-1.80 (m, 8 H). LC/MS(Cond.-D1): R_(t)=1.95 min; Anal. Calc. for [M+H]⁺ C₃₄H₃₉N₆O₇: 643.29;found: 643.37. HRMS: Anal. Calc. for [M+H]⁺ C₃₄H₃₉N₆O₇: 643.2880; found:643.2825.

Example D-61 and Example D-62

Prepared from Example D-57b and 1.0 eq of 2-(thiophen-2-yl)acetic acidand 1.0 eq. of acetic acid according to the procedure described forExample D-57. This afforded Example D-61 (14.9 mg, 11%) as an off-whitesolid and Example D-62 (39.8 mg, 34%) also as an off-white solid.Example D-55 was also isolated from the mixture (see above for itscharacterization data).

For Example D-61: ¹H NMR (DMSO-d₆, 400 MHz) δ 10.61 and 10.41 (2s, 2 H),8.10-8.06 (m, 4 H), 7.87-7.82 (m, 4H), 7.39-7.37 (2m, 2 H), 6.97-6.80(m, 4 H), 4.70-4.65 and 4.49-4.46 (2m, 2 H), 3.95 (br s, 4 H), 3.73-3.62(2m, 4 H), 2.35-2.15 (2m, 2 H), 2.07-1.90 (2m, 6 H). LC/MS (Cond.-D1):R_(t)=2.29 min; Anal. Calc. for [M+H]⁺ C₃₆H₃₅N₆O₅S₂: 695.21; found:695.19. HRMS: Anal. Calc. for [M+H]⁺ C₃₆H₃₅N₆O₅S₂: 695.2110; found:695.2109.

For Example D-62: ¹H NMR (DMSO-d₆, 400 MHz) δ 10.59, 10.53, 10.41 and10.35 (4s, 2H), 8.11-8.06 (m, 4H), 7.87-7.83 (m, 4H), 7.39-7.34 (m, 1H),6.97-6.86 (m, 2H), 4.73-4.54 and 4.49-4.41 (2m, 2H), 3.95 (s, 2H),3.71-3.51 (series of m, 4H), 2.37-2.10 (2m, 2H), 2.01 and 1.86 (2s, 3H),2.00-1.90 (m, 6H). LC/MS (Cond.-D1): R_(t)=2.09 min; Anal. Calc. for[M+H]⁺ C₃₂H₃₃N₆O₅S: 613.22; found: 613.20. HRMS: Anal. Calc. for [M+H]⁺C₃₂H₃₃N₆O₅S: 613.2233; found: 613.2223.

Example D-63 and Example D-64

Prepared from Example D-57b and 1.0 eq. of 2-(pyridin-3-yl)acetic acidand 1.0 eq. of acetic acid according to the procedure described forExample D-57. This afforded Example D-63 (19.4 mg, 15%) as an off-whitesolid and Example D-64 (38.4 mg, 33%) also as an off-white solid.Example D-55 was also isolated from the mixture (see above for itscharacterization data).

For Example D-63: ¹H NMR (MeOH-d₄, 400 MHz) δ 8.48-8.47 (m, 2 H),8.40-8.35 (m, 2 H), 8.01-7.96 and 7.80-7.77 (2m, 6 H), 7.75-7.70 and7.59-7.57 (2m, 4 H), 7.40-7.30 (2m, 2 H), 4.77-4.55 and 4.54-4.51 (2m, 2H), 3.87 (s, 4 H), 3.80-3.71 (m, 4 H), 2.21-2.12 (m, 4 H), 2.05-1.95 (m,4 H). LC/MS (Cond.-D1): R_(t)=1.58 min; Anal. Calc. for [M+H]⁺C₃₈H₃₇N₈O₅: 685.29. found: 685.40. HRMS: Anal. Calc. for [M+H]⁺C₃₈H₃₇N₈O₅: 685.2887; found: 685.2888.

For Example D-64: ¹H NMR (MeOH-d₄, 400 MHz) δ 8.47 (m, 1 H), 8.39-8.38(m, 1 H), 7.97-7.89 and 7.80-7.67 (2m, 5 H), 7.61-7.58 (m, 4 H),7.39-7.36 (m, 1 H), 4.58-4.51 (m, 2 H), 3.87 (s, 2 H), 3.80-3.58 (2m, 4H), 2.26-2.17 (m, 2 H), 2.13 and 1.98 (2s, 3 H), 2.04-1.95 (m, 6 H).LC/MS (Cond.-D1): R_(t)=1.68 min; Anal. Calc. for [M+H]⁺ C₃₃H₃₄N₇O₅:608.26; found: 608.23. HRMS: Anal. Calc. for [M+H]⁺ C₃₃H₃₄N₇O₅:608.2622; found: 608.2605.

Example OL-18

Example OL-18a

Pd(PPh₃)₂Cl₂ (10 mg, 0.013 mmol), copper (I) iodide (5 mg, 0.026 mmol),potassium carbonate (0.36 g, 2.26 mmol) and nBu₃N (31 μL, 0.131 mmol)were added to a suspension of p-nitro-iodobenzene (0.32 g, 1.31 mmol)and p-nitrophenyl-acetylene (0.25 g, 1.7 mmol) in a mixture of water (10mL) and dimethylformamide (10 mL). The mixture was stirred at ambienttemperature for 3 h and then it was extracted with diethyl ether. Thecombined organic layers were washed with brine, dried (MgSO₄), filteredand concentrated to give Example OL-18a (0.23 g, 98% yield) as a brownsolid, which was used without further purification. ¹H NMR (DMSO-d₆, 500MHz) δ 8.31 (d, J=8.8 Hz, 4 H), 7.91 (d, J=8.8 Hz, 4 H). LC/MS (Cond.OL1): R_(t)=1.79 min; Anal. Calc. for [M+H]⁺ C₁₄H₉N₂O₄: 269.05; found:179.

Example OL-18b

Example OL-18a (50 mg, 0.28 mmol) and sodium azide (22 mg, 0.34 mmol)were dissolved in dimethylformamide (2 mL) and heated under microwaveconditions at 220° C., for 30 min. The brown solution was evaporated andthe residue was taken up in ethyl acetate, washed with brine, dried(MgSO₄), filtered and concentrated to afford Example OL-18b (85 mg, 98%yield) as a brown solid that was used without further purification. ¹HNMR (DMSO-d₆, 500 MHz) δ 15.85 (bs, 1 H), 8.31 (d, J=8.8 Hz, 4 H), 7.79(d, J=8.8 Hz, 4 H). LC/MS (Cond. OL1): R_(t)=1.63 min; Anal. Calc. for[M+H]⁺ C₁₄H₁₀N₅O₄: 312.07; found: 312.

Example OL-18c

Prepared from Example OL-18b according to the procedure described forExample OL-1c. This afforded Example OL-18c (82 mg, 51% yield) as anoff-white solid. ¹H NMR (DMSO-d₆, 500 MHz) δ 14.98 (bs, 1 H), 7.15 (d,J=8.2 Hz, 4 H), 6.57 (d, J=8.2 Hz, 4 H), 5.21 (bs, 4 H). LC/MS (Cond.OL2): R_(t)=0.18 min; Anal. Calc. for [M+H]⁺ C₁₄H₁₄N₅: 252.12; found:252.

Example OL-18

Prepared from Example OL-18c and L-Cbz-Alanine according to theprocedure described for Example OL-1d. This afforded Example OL-18 (37mg, 56% yield) as an off-white solid. ¹H NMR (DMSO-d₆, 500 MHz) δ 10.13(s, 2 H), 7.64 (m, 6 H), 7.43 (d, J=8.8 Hz, 2H), 7.36 (m, 7 H), 7.31 (m,2 H), 7.25 (bs, 1 H), 7.18 (bs, 1 H), 5.03 (m, 4 H), 4.30 (dq, J=7.0 Hz,2 H), 1.30 (d, J=7.0 Hz, 6 H), LC/MS (Cond. OL2): R_(t)=5.48 min; Anal.Calc. for [M+H]⁺ C₃₆H₃₆N₇O₆: 662.26; found: 662.

Example OL-19

Prepared from Example OL-18c and Carbobenzyloxy-L-Proline according tothe procedure described for Example OL-1d. This afforded the TFA salt ofExample OL-19 (41 mg, 57% yield) as an off-white solid. ¹H NMR (DMSO-d₆,500 MHz) δ 10.18 (s, 2 H), 7.64 (m, 4 H), 7.43 (m, 4 H), 7.37 (d, J=3.6Hz, 4 H), 7.32 (m, 1 H), 7.22 (d, J=7.3 Hz, 2 H), 7.18 (t, J=7.3 Hz, 1H), 7.12 (q, J=7.0 Hz, 2 H), 5.09 (m, 3 H), 4.94 (d, J=13.1, 1 H), 4.37(m, 2 H), 3.51 (m, 2 H), 3.44 (m, 2 H), 2.25 (m, 2 H), 1.90 (m, 6 H).LC/MS (Cond. OL2): R_(t)=5.96 min; Anal. Calc. for [M+H]⁺ C40H₄₀N7O₆:714.30; found: 714.

Example OL-20

Prepared from Example OL-18c and(S)-1-(2-phenylacetyl)pyrrolidine-2-carboxylic acid according to theprocedure described for Example OL-1d. This gave the TFA salt of ExampleOL-20 (25 mg, 31% yield) as an off-white solid. ¹H NMR (DMSO-d₆, 500MHz) δ 10.12 and 10.23 (2s, 2 H), 7.62 (d, J=8.8 Hz, 4 H), 7.41 (d,J=8.5 Hz, 4 H), 7.24 (m, 10 H), 4.44 and 4.65 (2dd, J=8.5, 3.4, 2 H),3.71 (m, 4H), 3.62 (m, 5 H), 2.15 (m, 2 H), 2.01 (m, 2 H), 1.90 (m, 4H). LC/MS (Cond. OL2): R_(t)=6.00 min; Anal. Calc. for [M+H]⁺C₄₀H₄₀N₇O₄: 682.31; found: 682.

Example OL-21

Prepared from Example OL-18c and(2S,4R)-4-hydroxy-1-(2-phenylacetyl)pyrrolidine-2-carboxylic acidaccording to the procedure described for Example OL-1d. This affordedthe TFA salt of Example OL-21 (29 mg, 34% yield) as an off-white solid.¹H NMR (DMSO-d₆, 500 MHz) δ 10.17 and 10.39 (2s, 2 H), 7.69 (d, J=8.5Hz, 4 H), 7.48 (d, J=8.5 Hz, 4 H), 7.24 (m, 12 H), 5.12 (bs, 2 H), 4.50(q, J=7.8 Hz, 2 H), 4.39 (m, 2 H), 3.68 (m, 6 H), 3.51 (m, 4 H), 2.11(m, 2 H), 1.96 (m, 2 H). LC/MS (Cond. OL2): R_(t)=5.05 min; Anal. Calc.for [M+H]⁺ C₄₀H₄₀N₇O₆: 714.30; found: 714.

Example OL-22

Example OL-22a

n-Butyl lithium (21.1 mL, 30.6 mmol) was added dropwise to a solution ofthiophene (1.2 mL, 15 mmol) and tetramethylethylenediamine (4.62 mL,30.6 mmol) in hexanes (20 mL) at 0° C. The mixture was heated to refluxtemperature for 30 min and cooled down to 0° C. and trimethyltinchloride (1M in hexanes, 31.7 mL) was added slowly. The reaction mixturewas then stirred at ambient temperature overnight, followed by additionof saturated aqueous ammonium chloride and separation of both phases.The organic layer was washed twice with sat. aq. copper (II) sulfate,dried (MgSO₄), filtered and concentrated to afford a brown solid. Thesolid was recrystallized from hexanes to afford Example OL-22a (0.33 g,81% yield) as a white solid. ¹H NMR (CDCl₃, 500 MHz) δ 7.36 (s, 2 H),0.36 (m, 18 H).

Example OL-22b

Example OL-22a (0.24 g, 0.59 mmol), p-nitrobromobenzene (0.13 g, 0.65mmol) and Pd(PPh₃)Cl₂ (21 mg, 0.03 mmol) were combined intetrahydrofuran (10 mL) and heated to reflux temperature for 6 h. Theresulting suspension was diluted with hexanes, cooled to ambienttemperature and filtered. A red solid was collected and washed withhexanes to afford Example OL-22b (0.17 g, 88% yield) which was usedwithout further purification. ¹H NMR (DMSO-d₆, 500 MHz) δ 8.30 (d, J=8.8Hz, 4 H), 8.02 (d, J=8.8 Hz, 4 H), 7.94 (s, 2 H).

Example OL-22c

Prepared from Example OL-22b according to the procedure described forExample OL-1c. This afforded Example OL-22c (53 mg, 38% yield) as anoff-white solid. ¹H NMR (DMSO-d₆, 500 MHz) δ 7.29 (d, J=8.2 Hz, 4 H),7.09 (s, 2 H), 6.57 (d, J=8.2 Hz, 4 H), 5.28 (s, 4 H). LC/MS (Cond.OL2): R_(t)=0.83 min; Anal. Calc. for [M+H]⁺ C₁₆H₁₅N₂S: 267.09; found:267.

Example OL-22

Prepared from Example OL-22c and(S)-1-(2-phenylacetyl)pyrrolidine-2-carboxylic acid according to theprocedure described for Example OL-1d. This gave Example OL-22 (15 mg,15% yield) as an off-white solid. ¹H NMR (DMSO-d₆, 500 MHz) δ 10.11 and10.39 (2s, 2 H), 7.62 (m, 8 H), 7.42 (s, 2 H), 7.24 (m, 10 H), 4.44 and4.65 (2dd, J=8.1, 3.5, 2 H), 3.70 (m, 4 H), 3.61 (m, 4 H), 2.16 (m, 2H), 2.01 (m, 2 H), 1.91 (m, 4 H). LC/MS (Cond. OL2): R_(t)=2.00 min;Anal. Calc. for [M+H]⁺ C₄₂H₄₁N₄O₄S: 697.28; found: 697.

Example OL-23

Prepared from Example OL-22c and Carbobenzyloxy-L-Proline according tothe procedure described for Example OL-1d. This afforded Example OL-23(23 mg, 27% yield) as an off-white solid. ¹H NMR (DMSO-d₆, 500 MHz) δ10.17 (d, J=4.5 Hz, 2 H), 7.65 (m, 8 H), 7.45 (t, J=4.5 Hz, 2 H), 7.38(d, J=4.3 Hz, 4 H), 7.33 (m, 1H), 7.25 (d, J=7.3 Hz, 2 H), 7.19 (d,J=7.3 Hz, 1 H), 7.15 (d, J=7.3 Hz, 2 H), 5.09 (m, 3 H), 4.96 (d, J=12.8,1 H), 4.39 (dd, J=8.4, 3.2 Hz, 1H), 4.35 (dd, J=8.2, 3.0 Hz, 1 H), 3.53(m, 2 H), 3.46 (m, 2 H), 2.28 (m, 1 H), 2.22 (m, 1 H), 1.90 (m, 6 H).LC/MS (Cond. OL2): R_(t)=2.09 min; Anal. Calc. for [M+H]⁺ C₄₂H₄₀N₄NaO₆S:751.26; found: 751.

Example OL-24

Prepared from Example OL-22c and L-Acetyl-proline according to theprocedure described for Example OL-1d. This afforded Example OL-24 (51mg, 92% yield) as an off-white solid. ¹H NMR (DMSO-d₆, 500 MHz) δ 10.08and 10.27 (2s, 2 H), 7.64 (m, 8 H), 7.43 and 7.44 (2s, 2 H), 4.38 and4.51 (2dd, J=8.6, 3.1 Hz, 2 H), 3.51 (m, 4 H), 2.15 (m, 2 H), 1.92 (m, 4H), 1.83 (m, 2 H), 1.85 and 2.00 (2m, 6 H). LC/MS (Cond. OL1):R_(t)=1.59 min; Anal. Calc. for [M+H]⁺ C₃₀H₃₃N₄O₄S: 545.21; found: 545.

Example OL-25

Example OL-25a

Prepared from 2,5-bis(3-nitrophenyl)thiophene according to the proceduredescribed for Example OL-22c. This afforded Example OL-25a (81 mg, 66%yield) as an off-white solid. ¹H NMR (DMSO-d₆, 500 MHz) δ 7.31 (s, 2H),7.31 (s, 2 H), 7.05 (t, J=7.8 Hz, 2 H), 6.83 (m, 4 H), 6.51 (dd, J=7.8,1.3 Hz, 2H), 5.22 (s, 4 H). LC/MS (Cond. OL2): R_(t)=1.04 min; Anal.Calc. for [M+H]⁺ C₁₆H₁₅N₂S: 267.09; found: 267.

Example OL-25

Prepared from Example OL-25a and(S)-1-(2-phenylacetyl)pyrrolidine-2-carboxylic acid according to theprocedure described for Example OL-1d. This afforded Example OL-25 (41mg, 51% yield) as an off-white solid. ¹H NMR (DMSO-d₆, 500 MHz) M0.12and 10.33 (2s, 2 H), 8.05 (s, 2 H), 7.15-7.55 (m, 18 H), 4.45 and 4.65(2dd, J=8.2, 3.4, 2 H), 3.72 (m, 4 H), 3.68 (m, 2 H), 3.60 (m, 2 H),2.16 (m, 2 H), 2.03 (m, 2 H), 1.93 (m, 4 H). LC/MS (Cond. OL2):R_(t)=2.26 min; Anal. Calc. for [M+H]⁺ C₄₂H₄₁N₄O₄S: 697.28; found: 697.

Example OL-26

Example OL-26a

Prepared from 3,5-diphenyl-1H-pyrazole according to the proceduredescribed for Example OL-1b. This gave Example OL-25a (3.51 g, 98%yield) as a yellow solid. ¹H NMR (DMSO-d₆, 500 MHz) δ 13.07 (s, 1 H),8.25 (bs, 4 H), 8.03 (s, 1 H), 7.73 (d, J=7.0 Hz, 4 H). LC/MS (Cond.OL2): R_(t)=1.48 min; Anal. Calc. for [M+H]⁺ C₁₅H₁₁N₄O₄: 311.07. found:311.

Example OL-26b

Prepared from Example OL-26a according to the procedure described forExample OL-1c. This gave Example OL-26b (0.78 g, 97% yield) as anoff-white solid. ¹H NMR (DMSO-d₆, 500 MHz) δ 11.71 (bs, 1 H), 7.52 (s, 1H), 7.11 (m, 4 H), 6.48 (m, 4 H), 5.17 (bs, 2 H), 4.94 (bs, 2 H). LC/MS(Cond. OL2): R_(t)=0.87 min; Anal. Calc. for [M+H]⁺ C₁₅H₁₅N₄: 251.12;found: 251.

Example OL-26

Prepared from Example OL-26b and Carbobenzyloxy-L-Proline according tothe procedure described for Example OL-1d. This gave the TFA salt ofExample OL-26 (73 mg, 73% yield) as an off-white solid. ¹H NMR (DMSO-d₆,500 MHz) δ 10.16 (d, J=2.93 Hz, 2 H), 7.78 (m, 4 H), 7.67 (m, 4 H), 7.38(m, 4 H), 7.34 (m, 1 H), 7.24 (d, J=6.9 Hz, 2 H), 7.12 (m, 4 H), 5.09(m, 3 H), 4.96 (d, J=12.8, 1 H), 4.39 (m, 2 H), 3.49 (m, 4 H), 2.27 (m,2 H), 1.93 (m, 6 H). LC/MS (Cond. OL1): R_(t)=1.82 min; Anal. Calc. for[M+H]⁺ C₄₁H₄₁N₆O₆: 713.30; found: 713.

Example OL-27

Prepared from Example OL-26b and(S)-1-(2-phenylacetyl)pyrrolidine-2-carboxylic acid according to theprocedure described for Example OL-1d. This gave the TFA salt of ExampleOL-27 (61 mg, 64% yield) as an off-white solid. ¹H NMR (DMSO-d₆, 500MHz) δ 10.09 and 10.32 (2s, 2 H), 7.75 (d, J=8.8 Hz, 4 H), 7.65 (d,J=8.8 Hz, 4 H), 7.26 (m, 12 H), 4.45 (dd, J=8.2, 3.5 Hz, 2 H), 3.72 (s,4 H), 3.61 (m, 4 H), 2.15 (m, 2 H), 1.92 (m, 6 H). LC/MS (Cond. OL):R_(t)=1.71 min; Anal. Calc. for [M+H]⁺ C₄₁H₄₁N₆O₄: 681.31. found: 681.

Example OL-28

Prepared from Example OL-26b and(2S,4R)-4-hydroxy-1-(2-phenylacetyl)pyrrolidine-2-carboxylic acidaccording to the procedure described for Example OL-1d. This gave theTFA salt of Example OL-28 (69 mg, 69% yield) as an off-white solid. ¹HNMR (DMSO-d₆, 500 MHz) δ 10.12 and 10.37 (2s, 2 H), 7.75 (d, J=8.5 Hz, 4H), 7.65 (d, J=8.5 Hz, 4 H), 7.25 (m, 10 H), 7.03 and 7.05 (2s, 1 H),5.26 (bs, 2 H), 4.51 and 4.74 (2t, J=7.8 Hz, 2H), 4.32 and 4.40 (2m, 2H), 3.69 (m, 4 H), 3.15 (m, 4 H), 2.15 (m, 2 H), 1.97 (m, 2 H). LC/MS(Cond. OL1): R_(t)=1.47 min; Anal. Calc. for [M+H]⁺ C₄₁H₄₁N₆O₆: 713.30;found: 713.

Example OL-29

Prepared from Example OL-26b and L-Acetyl-proline according to theprocedure described for Example OL-1d. This gave the TFA salt of ExampleOL-29 (63 mg, 60% yield) as an off-white solid. ¹H NMR (DMSO-d₆, 500MHz) δ 10.46 and 10.66 (2s, 2 H), 8.18 and 8.19 (2d, J=8.8 Hz, 4 H),8.08 and 8.10 (2d, J=8.8 Hz, 4 H), 7.47 and 7.48 (2s, 1 H), 4.84 and4.95 (2dd, J=8.5, 3.7 Hz, 2 H), 4.03 (m, 2 H), 3.96 (m, 1 H), 3.88 (m, 1H), 2.57 (m, 2 H), 2.35 (m, 4 H), 2.28 and 2.41 (2m, 6H), 2.26 (m, 2 H).LC/MS (Cond. OL3): R_(t)=1.24 min; Anal. Calc. for [M+H]⁺ C₂₉H₃₃N₆O₄:529.25; found: 529.

Example OL-30

Example OL-30a

Prepared from Example OL-26b and L-Acetyl-proline and(S)-1-(tert-butoxycarbonyl)-2,5-dihydro-1H-pyrrole-2-carboxylic acidaccording to the procedure described for Example OL-1d. This gaveExample OL-30a (51 mg, 66% yield) as an off-white solid. ¹H NMR(DMSO-d₆, 500 MHz) δ 10.24 and 10.44 (2s, 2 H), 9.19 (bs, 1 H), 7.68 (m,4 H), 7.41 (m, 4 H), 6.10 (dd, J=6.3, 1.7 Hz, 2 H), 5.88 and 5.94 (2m, 2H), 5.09 and 5.27 (2dd, J=4.7, 2.3 Hz, 2 H), 4.37 (m, 3 H), 4.15 (m, 1H), 1.41 and 1.27 (2s, 18 H). LC/MS (Cond. OL1): R_(t)=1.02 min; Anal.Calc. for [M+H]⁺ C₃₅H₄₁N₆O₆: 641.30; found: 641.

Example OL-30b

Prepared from Example OL-30a according to the procedure described forExample D-47d. This afforded Example OL-30b (0.11 mg, 80% yield) as abrown solid. ¹H NMR (DMSO-d₆, 500 MHz) δ 10.24 and 10.44 (2s, 2 H), 9.19(bs, 1 H), 7.68 (m, 4 H), 7.41 (m, 4 H), 6.10 (dd, J=6.3, 1.7 Hz, 2 H),5.88 and 5.94 (2m, 2 H), 5.09 and 5.27 (2dd, J=4.7, 2.3 Hz, 2 H), 4.37(m, 3 H), 4.15 (m, 1 H), 3.30 (bs, 2H). LC/MS (Cond. OL1): R_(t)=0.84min; Anal. Calc. for [M+H]⁺ C₂₅H₂₅N₆O₂: 441.20; found: 441.

Example OL-30

Acetyl chloride (27 μL, 0.51 g, 0.375 mmol) was added slowly to asolution of OL-30b (75 mg, 0.17 mmol) and triethylamine (71 μL, 0.51mmol) in anhydrous methylene chloride (3 mL). The mixture was stirred atambient temperature for 0.5 h and poured into water. The aqueous layerwas extracted with ethyl acetate and the combined layers were dried(MgSO₄), filtered and concentrated. The remaining residue was purifiedby preparative HPLC on a C18-reverse phase column (MeOH/H₂O/TFA) toafford the TFA salt of Example OL-30 (51 mg, 66% yield) as an off-whitesolid. ¹H NMR (DMSO-d₆, 500 MHz) δ 10.24 and 10.44 (2s, 2 H), 9.19 (bs,1 H), 7.68 (m, 4 H), 7.41 (m, 4 H), 6.10 (dd, J=6.3, 1.7 Hz, 2 H), 5.88and 5.94 (2m, 2 H), 5.09 and 5.27 (2dd, J=4.7, 2.3 Hz, 2 H), 4.37 (m, 3H), 4.15 (m, 1 H), 1.88 and 2.03 (2s, 6 H). LC/MS (Cond. OL1):R_(t)=1.45 min; Anal. Calc. for [M+H]⁺ C₂₉H₂₉N₆O₄: 525.23; found: 525.

Example OL-31

Example OL-31a

Prepared from Example OL-26b and(S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid according tothe procedure described for Example OL-1d. This gave Example OL-31a(0.43 g, 73%) as an off-white solid. ¹H NMR (DMSO-d₆, 500 MHz) δ 10.16(d, J=2.93 Hz, 2 H), 8.08 (m, 4 H), 7.67 (m, 4 H), 7.34 (m, 1 H), 4.39(m, 2 H), 3.49 (m, 4 H), 2.27 (m, 2 H), 1.93 (m, 6 H), 1.41 and 1.27(2s, 18 H). LC/MS (Cond. OL3): R_(t)=1.49 min; Anal. Calc. for [M+H]⁺C₃₅H₄₅N₆O₆: 645.33; found: 645.

Example OL-31b

Trifluoroacetic acid (2 mL) was added to a solution of OL-31a (0.43 g,0.67 mmol) in anhydrous methylene chloride (20 mL) and the resultingsolution was stirred at ambient temperature for 2 h. The solvent andexcess trifluoroacetic acid were removed under reduced pressure and theresulting brown solid was free-based using UCT MCX cartridges (2.0 g)and methanol, to give Example OL-31b (026 g, 87%) as a brown solid. ¹HNMR (DMSO-d₆, 500 MHz) δ 10.16 (sz, 2 H), 8.08 (m, 4 H), 7.67 (m, 4 H),7.34 (m, 1 H), 4.39 (m, 2 H), 3.49 (m, 4 H), 2.50 (bs, 2 H), 2.24 (m, 2H), 1.95 (m, 6 H). LC/MS (Cond. OL3): R_(t)=0.77 min; Anal. Calc. for[M+H]⁺ C₂₅H₂₉N₆O₂: 445.23; found: 445.

Example OL-31

Prepared from Example OL-31b and isobutyryl chloride according to theprocedure described for Example OL-30. This gave the TFA salt of ExampleOL-31 (43 mg, 63% yield) as an off-white solid. ¹H NMR (DMSO-d₆, 500MHz) δ 10.17 and 10.35 (2s, 2 H), 9.23 (bs, 1 H), 7.68 (d, J=8.5 Hz, 4H), 7.40 (m, 4 H), 4.40 and 4.58 (2dd, J=8.5, 3.9 Hz, 2 H), 3.61 (m, 3H), 3.46 (m, 1 H), 2.73 (qq, J=6.7 Hz, 2 H), 2.14 (m, 2 H), 2.01 (m, 2H), 1.88 (m, 4 H), 1.02 (d, J=6.7 Hz, 6 H), 1.00 (d, J=6.7 Hz, 6 H).LC/MS (Cond. OL1): R_(t)=2.27 min; Anal. Calc. for [M+H]⁺ C₃₃H₄₁N₆O₄:585.31; found: 585.

Example OL-32

Prepared from Example OL-31b and propionyl chloride according to theprocedure described for Example OL-30. This gave the TFA salt of ExampleOL-32 (33 mg, 44% yield) as an off-white solid. ¹H NMR (DMSO-d₆, 500MHz) δ 10.17 and 10.34 (2s, 2 H), 9.22 (bs, 1 H), 7.68 (d, J=8.5 Hz, 4H), 7.40 (m, 4 H), 4.41/4.52 (dd, J=8.3, 3.8 Hz, 2 H), 3.54 (m, 4 H),2.31 (q, J=7.5 Hz, 4 H), 2.13 (m, 2 H), 2.00 (m, 2 H), 1.91 (m, 4 H),0.98 (t, J=7.5 Hz, 6 H). LC/MS (Cond. OL1): R_(t)=1.99 min; Anal. Calc.for [M+H]⁺ C₃₁H₃₇N₆O₄: 557.28; found: 557.

Example OL-33

Prepared from Example OL-31b and cyclobutanecarbonyl chloride accordingto the procedure described for Example OL-30. This gave the TFA salt ofExample OL-33 (47 mg, 57% yield) as an off-white solid. ¹H NMR (DMSO-d₆,500 MHz) δ 10.20 and 10.30 (2s, 2 H), 7.69 (d, J=8.5 Hz, 4 H), 7.40 (m,4 H), 4.40 and 4.45 (2dd, J=8.4, 3.8 Hz, 2 H), 3.45 (m, 5 H), 3.31 (q,J=8.5 Hz, 2 H), 2.11 (m, 9 H), 1.91 (m, 8 H), 1.74 (m, 2 H). LC/MS(Cond. OL1): R_(t)=2.44 min; Anal. Calc. for [M+H]⁺ C₃₅H₄₁N₆O₄: 609.31;found: 609.

Example OL-34

Prepared from Example OL-31b and isonicotinoyl chloride according to theprocedure described for Example OL-30. This gave the TFA salt of ExampleOL-34 (36 mg, 41% yield) as an off-white solid. ¹H NMR (DMSO-d₆, 500MHz) δ 9.97 and 10.35 (2s, 2 H), 9.28 (bs, 1 H), 8.72 (m, 3 H), 8.56 (m,1 H), 7.73 (d, J=8.5 Hz, 3 H), 7.52 (d, J=5.5 Hz, 3 H), 7.41 (m, 4 H),7.35 (m, 2 H), 4.40 and 4.61 (2dd, J=8.1, 4.7 Hz, 2 H), 3.65 (m, 1 H),3.51 (m, 3 H), 2.30 (m, 2 H), 1.97 (m, 4 H), 1.88 (m, 2 H). LC/MS (Cond.OL1): R_(t)=1.50 min; Anal. Calc. for [M+H]⁺ C₃₇H₃₅N₈O₄: 655.27; found:655.

Example OL-35

Prepared from Example OL-31b and cyclopropanecarbonyl chloride accordingto the procedure described for Example OL-30. This gave the TFA salt ofExample OL-35 (29 mg, 37% yield) as an off-white solid. ¹H NMR (DMSO-d₆,500 MHz) δ 10.19 and 10.33 (2s, 2 H), 9.19 (bs, 1 H), 7.67 (m, 4 H),7.39 (m, 4 H), 4.42 and 4.73 (2dd, J=8.4, 3.8 Hz, 2 H), 3.78 (m, 3 H),3.72 (m, 2 H), 2.18 (m, 1 H), 2.06 (m, 2 H), 1.95 (m, 3 H), 1.83 (m, 2H), 0.73 (m, 8 H). LC/MS (Cond. OL1): R_(t)=2.08 min; Anal. Calc. for[M+H]⁺ C₃₃H₃₇N₆O₄: 581.28; found: 581.

Example OL-36

Prepared from Example OL-31b according to the procedure described forExample OL-30 using a 1:1 mixture of the corresponding acid chlorides.This gave the TFA salt of Example OL-36 (25 mg, 30% yield) as anoff-white solid. ¹H NMR (DMSO-d₆, 500 MHz) δ 10.06 and 10.21 (2s, 1 H),10.02 and 10.21 (2s, 2 H), 7.77 (m, 4 H), 7.66 (m, 4 H), 7.25 (m, 5 H),7.04 (m, 1 H), 4.46 and 4.67 (2dd, J=8.5, 3.7, 1 H), 4.42 and 4.52 (2dd,J=8.5, 3.4, 1 H), 3.73 (s, 2 H), 3.66 (m, 1 H), 3.61 (m, 2 H), 3.53 (m,1 H), 3.43 (m, 1 H), 2.15 (m, H H), 1.99 (m, 2 H), 1.91 (m, 3 H), 1.87and 2.01 (2s, 3 H). LC/MS (Cond. OL3): R_(t)=2.67 min; Anal. Calc. for[M+H]⁺ C₃₅H₃₇N₆O₄: 605.28; found: 605.

Example OL-37

Prepared from Example OL-30b and cyclopropanecarbonyl chloride accordingto the procedure described for Example OL-30. This afforded the TFA saltof Example OL-37 (44 mg, 56% yield) as an off-white solid. ¹H NMR(DMSO-d₆, 500 MHz) δ 10.27 and 10.40 (2s, 2 H), 9.20 (bs, 1 H), 7.67 (m,4 H), 7.40 (m, 4 H), 6.14 (m, 2 H), 5.90 and 5.98 (2m, 2 H), 5.13 and5.46 (2m, 2 H), 4.53 (m, 3 H), 4.22 (m, 1 H), 2.49 (m, 1 H), 1.83 (m, 1H), 0.76 (m, 7 H). LC/MS (Cond. OL3): R_(t)=1.18 min; Anal. Calc. for[M+H]⁺ C₃₃H₃₃N₆O₄: 577.25; found: 577.

Example OL-38

Prepared from Example OL-30b and cyclobutanecarbonyl chloride accordingto the procedure described for Example OL-30. This gave the TFA salt ofExample OL-38 (52 mg, 63% yield) as an off-white solid. ¹H NMR (DMSO-d₆,500 MHz) δ 10.29 and 10.39 (2s, 2 H), 9.20 (bs, 1 H), 7.68 (d, J=8.8 Hz,4 H), 7.41 (m, 4H), 6.09 (m, 2 H), 5.89 and 5.91 (2dd, J=6.3, 1.9, 2 H),5.11 and 5.19 (2dd, J=4.6, 2.1 Hz, 2 H), 4.24 (m, 4 H), 3.34 (tt, J=8.2Hz, 2 H), 2.14 (m, 8 H), 1.94 (m, 2 H), 1.77 (m, 2 H). LC/MS (Cond.OL3): R_(t)=1.34 min; Anal. Calc. for [M+H]⁺ C₃₅H₃₇N₆O₄: 605.28; found:605.

Example OL-39

Prepared from Example OL-30b and 2-cyclopentylacetyl chloride accordingto the procedure described for Example OL-30. This afforded the TFA saltof Example OL-39 (26 mg, 29% yield) as an off-white solid. ¹H NMR(DMSO-d₆, 500 MHz) δ 10.26 and 10.41 (2s, 2 H), 9.18 (bs, 1 H), 7.67 (d,J=8.8 Hz, 4 H), 7.41 (m, 4 H), 6.09 (dd, J=6.4, 2.0 Hz, 2 H), 5.89 (dd,J=6.4, 2.0, 1 H), 5.10 (m, 1 H), 4.35 (m, 3 H), 2.34 (m, 4 H), 2.16 (m,4 H), 1.54 (m, 8 H), 1.14 (m, 4 H). LC/MS (Cond. OL3): R_(t)=1.64 min;Anal. Calc. for [M+H]⁺ C₃₉H₄₅N₆O₄: 661.34; found: 661.

Example OL-40

Et₃N (64 μL, 0.46 mmol) was added to a suspension of Example OL-31b,3-chloroisoquinoline-1-carboxylic acid (Cap 145) (49 mg, 0.235 mmol),HOBT (32 mg, 0.235 mmol) and EDCI (45 mg, 0.235 mmol) in DMF (3 mL) andthe resulting solution was stirred at ambient temperature overnight. Thereaction mixture was concentrated under vacuo and the remaining residuewas purified by reverse phase preparative HPLC (solvent system: H₂O,MeOH/TFA) and the TFA salt of Example OL-40 was isolated as a whitesolid (43 mg, 45% yield). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 10.44 and 9.64(2s, 2 H) 8.30 (d, J=8.55 Hz, 2 H) 8.12-8.23 (m, 2H) 8.06 (t, J=9.31 Hz,2 H) 7.91 (t, J=7.48 Hz, 2 H) 7.67-7.87 (m, 8 H) 7.56 (d, J=8.24 Hz, 1H) 6.99-7.13 (m, 2 H) 4.79 and 4.45 (m, 2 H) 3.82 (br. s., 1 H)3.30-3.42 (m, 2 H) 3.17-3.29 (m, 2 H) 2.29-2.45 (m, 2 H) 1.81-2.12 (m, 6H). LCMS (cond. OL3): R_(t)=1.87 min Anal.Calcd. for [M+H]⁺:C₄₅H₃₇Cl₂N₈O₄ 822.23. Found: 822.96; HRMS: Anal. Calcd. for:C₄₅H₃₇Cl₂N₈O₄ (M+H)⁺ 823.2315; Found: 823.2319.

Examples OL-41 to OL-42

Examples OL-41 to OL-42 were prepared from Example OL-31b and 2.0 eq. ofthe appropriate, commercially-available or synthesized carboxylic acidsaccording to the procedure described for the preparation of ExampleOL-40. Purification of the final targets was accomplished using aShimadzu reverse phase preparative HPLC instrument (solvent systems:H₂O/MeOH/TFA or H₂O/ACN/TFA) and the final products were isolated as TFAsalts.

Example RCOOH Conditions OL-41

  Cap 151 LCMS: Anal. Calcd. for (M + H)⁺: C₄₇H₄₁Cl₂N₈O₆ 883.25; Found:683.43 HRMS: Anal. Calcd. for (M − H)⁺ C₄₇H₃₉Cl₂N₈O₆: 881.2370; Found:881.2401 R_(t) = 2.17 min (Cond. OL3) OL-42

  Cap 130 LCMS: Anal. Calcd. for (M + H)⁺: C₄₅H₄₇N₈O₆ 795.36; Found:795.78 HRMS: Anal. Calcd. for (M + H)⁺ C₄₅H₄₇N₈O₆: 765.3619; Found:795.3604 R_(t) = 1.80 min (Cond. OL3)

Example OL-43

Example OL-43a

To a mixture of Example OL-26b (0.6 g, 2.4 mmol) and Boc-L-alanine (0.95g, 5.04 mmol) in dichloromethane (75 ml) was added EEDQ (1.30 g, 5.28mmol). The mixture was stirred at ambient temperature for 16 h. Thesolvent was removed in vacuo and the residue was triturated hexanes. Theresulting brown solid was filtered and dried under vacuo. Example OL-43a(1.15 g, 81% yield) was used without further purification. ¹H NMR (500MHz, DMSO-d₆) δ ppm 9.83-10.18 (m, 2 H) 7.55-7.87 (m, 8 H) 7.09 (br. s.,2 H) 7.03 (s, 1 H) 4.12 (qd, J=6.92, 6.71 Hz, 2H) 1.38 (s, 18 H) 1.27(d, J=7.02 Hz, 6 H). LC/MS (Cond. OL1): R_(t)=1.94 min; Anal. Calc. for[M+H]⁺ C₃₁H₄₁N₆O₆: 593.31; found: 593.

Example OL-43b

To a solution of Example OL-43a (1.15 g, 1.94 mmol) in dichloromethane(50 mL) was added 4N HCl in dioxane (10 ml). The reaction mixture wasstirred at ambient temperature for 4 h before it was concentrated undervacuo. The residue was triturated with ether (100 ml), filtered anddried in vacuo to afford Example OL-43b as an orange solid (0.97 g,quant.) which was used without further purification. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 10.92 (s, 2 H) 8.35 (d, J=4.58 Hz, 6 H) 7.81 (d, 4H) 7.72(d, J=8.55 Hz, 4 H) 7.08 (s, 1 H) 4.04-4.15 (m, 2 H) 3.55 (s, 1 H) 1.48(d, J=7.02 Hz, 6 H). LC/MS (Cond. OL1): R_(t)=0.95 min; Anal. Calc. for[M+H]⁺ C₂₁H₂₅N₆O₂: 393.20; found: 393.08.

Example OL-43

DIEA (63 μL, 0.38 mmol) was added to a suspension of Example OL-43b (50mg, 0.1 mmol), S-mandelic acid (30.4 mg, 0.2 mmol), HOBT (27 mg, 0.2mmol) and EDCI (38 mg, 0.2 mmol) in DMF (3 mL) and the resultingsolution was stirred at ambient temperature overnight. The reactionmixture was concentrated under vacuo and the remaining residue waspurified by reverse phase preparative HPLC (solvent system: H₂O,MeOH/TFA) and the TFA salt of Example OL-43 was isolated as a yellowishsolid (42 mg, 54% yield) ¹H NMR (500 MHz, DMSO-d₆) δ ppm 10.13 (br. s.,2 H) 8.10 (d, J=7.63 Hz, 2 H) 7.76 (d, J=8.24 Hz, 4 H) 7.65 (d, J=8.55Hz, 4H) 7.42 (d, J=7.63 Hz, 4 H) 7.33 (t, J=7.48 Hz, 4 H) 7.24-7.29 (m,2 H) 7.05 (s, 1 H) 4.97 (s, 2 H) 4.44-4.53 (m, 2 H) 1.33 (d, J=7.02 Hz,6 H). LCMS (cond. OL3): R_(t)=1.81 min Anal.Calcd. for [M+H]⁺C₃₇H₃₇N₆O₆: 661.27; Found: 661.22; HRMS: Anal. Calcd. for: C₃₇H₃₅N₆O₆(M−H)⁺659.2618; Found: 659.2642.

Examples OL-44 to OL-48

Examples OL-44 to OL-48 were prepared from Example OL-43b and 2.0 eq. ofthe appropriate, commercially-available or synthesized carboxylic acidsaccording to the procedure described for the preparation of ExampleOL-43. Purification of the final targets was accomplished using aShimadzu reverse phase preparative HPLC instrument (solvent systems:H₂O/MeOH/TFA or H₂O/ACN/TFA) and the final products were isolated as TFAsalts.

Example RCOOH Conditions OL-44

LCMS: Anal. Calcd. for (M + H)⁺: C₃₇H₃₇N₆O₆ 661.27; Found: 661.22; HRMS:Anal. Calcd. for (M + H)⁺ C₃₇H₃₇N₆O₆: 661.2775; Found: 661.2755 R_(t) =1.75 min (Cond. OL3) OL-45

LCMS: Anal. Calcd. for (M + H)⁺: C₃₉H₄₁N₆O₆ 689.31; Found: 689.26; HRMS:Anal. Calcd. for (M + H)⁺ C₃₉H₄₁N₆O₆: 689.3088; Found: 689.3084 R_(t) =1.95 min (Cond. OL3) OL-46

LCMS: Anal. Calcd. for (M + H)⁺: C₃₉H₄₁N₆O₆ 689.31; Found: 689.39; HRMS:Anal. Calcd. for (M − H)⁻C₃₉H₃₉N₆O₆: 687.2931; Found: 687.2947 R_(t) =1.85 min (Cond. OL3) OL-47

LCMS: Anal. Calcd. for (M + H)⁺: C₄₃H₃₅Cl₂N₆O₄ 769.21; Found: 769.14HRMS: Anal. Calcd. for (M + H)⁺ C₄₃H₃₅Cl₂N₆O₄: 769.2097; Found: 769.2096R_(t) = 2.17 min (Cond. OL3) OL-48

LCMS: Anal. Calcd. for (M + H)⁺: C₄₁H₃₃Cl₂N₈O₄ 771.20; Found: 771.15;HRMS: Anal. Calcd. for (M + H)⁺ C₄₁H₃₃Cl₂N₈O₄: 771.2002; Found: 771.1977R_(t) = 2.19 min (Cond. OL3)

Example OL-49

To a mixture of Example OL-31b (62 mg, 0.25 mmol) and(2S,4R)-1-(benzyloxycarbonyl)-4-tert-butoxypyrrolidine-2-carboxylic acid(0.175 g, 0.54 mmol) in dichloromethane (5 ml) was added EEDQ (0.141 g,0.57 mmol). The mixture was stirred at ambient temperature for 16 h. Thesolvent was removed in vacuo and the residue purified by flashchromatography eluting with 30% to 50% EtOAc/hexanes, obtaining ExampleOL-49 as an off-white solid (0.126 g, 60%). ¹H NMR (500 MHz, DMSO-d₆) δppm 13.19 (br. s., 1 H) 10.24 (d, J=2.44 Hz, 1 H) 10.16 (d, J=8.85 Hz, 1H) 7.59-7.85 (m, 8 H) 7.30-7.43 (m, 5 H) 6.98-7.25 (m, 6 H) 5.02-5.16(m, 3 H) 4.96 (d, J=13.12 Hz, 1 H) 4.33-4.53 (m, 4 H) 3.65 (td, J=10.91,5.34 Hz, 2 H) 2.00-2.24 (m, 4 H) 1.17 (s, 9 H) 1.15 (s, 9 H). LC/MS(Cond. OL1): R_(t)=2.25 min; Anal. Calc. for [M+H]⁺ C₄₉H₅₆N₆O₈: 857.42;found: 857.38.

Examples OL-50 to OL-53

Examples OL-50 to OL-53 were prepared from Example JR-D-1d and 2.0 eq.of the appropriate, commercially-available or synthesized carboxylicacids according to the procedure described for the preparation ofExample JR-D-1. Purification of the final targets was accomplished usinga Shimadzu reverse phase preparative HPLC instrument (solvent systems:H₂O/MeOH/TFA or H₂O/ACN/TFA) and the final products were isolated as TFAsalts. The coupling partner (ROH) was obtained from commercial sourcesunless otherwise noted.

Example RCOOH Conditions OL-50

LCMS: Anal. Calcd. for (M + H)⁺: C₃₇H₃₂F₂N₇O₅ 692.24; Found: 692.20;HRMS: Anal. Calcd. for (M + H)⁺ C₃₇H₃₂F₂N₇O₅: 692.2433; Found: 692.2402R_(t) = 1.83 min (Cond. OL3) OL-51

LCMS: Anal. Calcd. for (M + H)⁺: C₄₅H₄₉N₇O₅ 768.39; Found: 768.35; HRMS:Anal. Calcd. for (M + H)⁺ C₄₅H₄₉N₇O₅: 768.3873; Found: 768.3889; R_(t) =1.43 min (Cond. OL3) OL-52

LCMS: Anal. Calcd. for (M + H)⁺: C₄₇H₄₀Cl₂N₇O₇ 884.24; Found: 884.42;HRMS: Anal. Calcd. for (M − H)⁻ C₄₇H₃₈Cl₂N₇O₇: 882.2210; Found: 882.2207R_(t) = 1.85 min (Cond. OL3) OL-53

LCMS: Anal. Calcd. for (M + H)⁺: C₄₅H₄₆N₇O₇ 766.34; Found: 796.75; HRMS:Anal. Calcd. for (M + H)⁺ C₄₅H₄₆N₇O₇: 796.3459; Found: 796.3481; R_(t) =2.17 min (Cond. OL3)

Examples OL-54 to OL-57

Examples OL-54 to OL-57 were prepared following the procedures for thepreparation of Examples OL-43 to OL-48 but using Example JR-D-1d asstarting material. The following final products were prepared using theappropriate, commercially-available or synthesized carboxylic acidsaccording to the procedure described for the preparation of ExampleOL-43. Purification of the final targets was accomplished using aShimadzu reverse phase preparative HPLC instrument (solvent systems:H₂O/MeOH/TFA or H₂O/ACN/TFA).

Example RCOOH Conditions OL-54

LCMS: Anal. Calcd. for (M + H)⁺: C₃₇H₃₆N₅O₇ 662.26; Found: 662.70; HRMS:Anal. Calcd. for (M + H)⁺ C₃₇H₃₆N₅O₇: 662.2615; Found: 662.2616; R_(t) =1.90 min (Cond. OL3) OL-55

LCMS: Anal. Calcd. for (M + H)⁺: C₃₇H₃₆N₅O₇ 662.26; Found: 662.70; HRMS:Anal. Calcd. for (M + H)⁺ C₃₇H₃₆N₅O₇: 662.2615; Found: 662.2616; R_(t) =1.85 min (Cond. OL3) OL-56

LCMS: Anal. Calcd. for (M + H)⁺: C₃₉H₄₀N₅O₇ 690.29; Found: 690.07; HRMS:Anal. Calcd. for (M + H)⁺ C₃₉H₄₀N₅O₇: 690.2928; Found: 690.2939; R_(t) =2.00 min (Cond. OL3) OL-57

LCMS: Anal. Calcd. for (M + H)⁺: C₃₉H₄₀N₅O₇ 690.29; Found: 690.48; HRMS:Anal. Calcd. for (M + H)⁺ C₃₉H₄₀N₅O₇: 690.2928; Found: 690.2897; R_(t) =1.97 min (Cond. OL3)

Examples OL-58 to OL-60

Examples OL-58 to OL-60 were prepared following the procedures for thepreparation of Examples OL-50 to OL-53 replacing Boc-(L)-proline for(2S,4R)-1-(tert-butoxycarbonyl)-4-methoxypyrrolidine-2-carboxylic acidas starting material. The following final products were prepared usingthe appropriate, commercially-available or synthesized carboxylic acidsaccording to the procedure described for the preparation of ExampleOL-43. Purification of the final targets was accomplished using aShimadzu reverse phase preparative HPLC instrument (solvent systems:H₂O/MeOH/TFA or H₂O/ACN/TFA) and Example OL-59 was isolated as a TFAsalt.

Example RCOOH Conditions OL-58

LCMS: Anal. Calcd. for (M + H)⁺: C₄₃H₄₄N₅O₉ 774.31; Found: 774.31; HRMS:Anal. Calcd. for (M + H)⁺ C₄₃H₄₄N₅O₉: 774.3139; Found: 774.3101; R_(t) =1.77 min (Cond. OL3) OL-59

LCMS: Anal. Calcd. for (M + H)⁺: C₄₇H₅₄N₇O₇ 828.41; Found: 828.47; HRMS:Anal. Calcd. for (M + H)⁺ C₄₇H₅₄N₇O₇: 828.4085; Found: 828.4075; R_(t) =1.34 min (Cond. OL3) OL-60

LCMS: Anal. Calcd. for (M + H)⁺: C₄₇H₅₀N₇O₉ 856.37; Found: 856.42; HRMS:Anal. Calcd. for (M + H)⁺ C₄₇H₅₀N₇O₉: 856.3670; Found: 856.3649; R_(t) =1.83 min (Cond. OL3)

Example OL-61

Example OL61a

Prepared from Example MS-1b and 1-Boc-Proline according to the proceduredescribed for Example MS-1c. This afforded Example OL61-a (530 mg) as ayellow solid. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 10.21 (1 H, bs), 8.36-8.42(2 H, m), 8.28-8.33 (2 H, m), 7.81-7.91 (3 H, m), 7.73-7.79 (2 H, m),4.17-4.30 (1 H, m), 3.39-3.46 (1 H, m), 3.33-3.38 (1 H, m), 2.13-2.26 (1H, m), 1.75-1.97 (3 H, m), 1.25-1.44 (9 H, m). LC (Cond.-OL4):R_(t)=2.14 min; LRMS: Anal. Calc. for [M+H]⁺ C₂₅H₂₇N₄O₆: 479.19;found:Molecule does not ionize well.

Example OL61-b

A cold (0° C.) solution of 4N HCl in dioxane (5 mL) was added to ExampleOL-61a (478 mg, 1.88 mmol) dissolved in CH₂Cl₂ (30 mL). The mixture wasstirred rapidly at 0° C. for 0.5 h before it was allowed to warm up toroom temperature. After 15 h at room temperature, the mixture wastriturated with Et₂O, filtered and concentrated in vacuo to afford theHCl salt of Example OL-61b (780 mg, 97%) as an orange solid ¹H NMR (500MHz, DMSO-d₆) δ ppm 10.88 (1 H, br. s.), 8.38-8.43 (2 H, m), 8.31-8.35(2 H, m), 7.87-7.96 (3 H, m), 7.79 (2 H, d, J=8.9 Hz), 4.56 (1H, t,J=5.6 Hz), 4.31-4.41 (1 H, m), 3.49 (2 H, q, J=5.2 Hz), 3.39-3.44 (3 H,m), 2.36-2.45 (1 H, m), 1.91-2.05 (3 H, m). LC (Cond.-OL4): R_(t)=1.56min; LRMS: Anal. Calc. for [M+H]⁺ C₂₀H₁₉N₄O₄: 379.14; found: Moleculedoes not ionize well.

Example OL61-c

Prepared from Example OL-61b and Cap-15, according to the proceduredescribed for Example D-57. This afforded Example OL61-c (597 mg) as ayellow solid. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 9.75-10.60 (1 H, m),8.36-8.44 (2 H, m), 8.27-8.35 (2 H, m), 8.04-8.12 (1 H, m), 7.90 (2 H,dd, J=6.6, 1.4 Hz), 7.81-7.87 (2 H, m), 7.55-7.77 (2 H, m), 7.17-7.39 (1H, m), 4.42-4.83 (1 H, m), 3.87-4.08 (3 H, m), 3.18-3.27 (1 H, m),2.29-2.45 (1 H, m), 2.00-2.10 (1 H, m), 1.84-1.97 (2 H, m). LC(Cond.-OL1): R_(t)=2.01 min; LRMS: Anal. Calc. for [M]⁺ C₃₁H₂₄ClN₅O₆:597.14; found: 597.78.

Example OL61-d

Prepared from Example OL-61c according to the procedure described forExample MS1-d. This afforded Example OL61-d (568 mg) as an off-whitesolid. LC (Cond.-J1): R_(t)=2.14 min; LRMS: Anal. Calc. for [M+H]⁺C₃₁H₂₇ClN₅O₄: 568.18. found: 568.53. HRMS: Anal. Calc. for [M+H]⁺C₃₁H₂₇ClN₅O₄: 568.11752; found: 568.1754.

Example OL61

Prepared from Example OL61-d, L-Boc Proline and Cap 1, according to theprocedure described for Example MS-7. This afforded Example OL61 (15 mg)as a pale yellow solid. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 10.53 (2 H, br.s.), 10.27 (1 H, br. s.), 7.99-8.13 (4 H, m), 7.69-7.88 (10 H, m),7.54-7.64 (7 H, m), 7.35 (1 H, d, J=7.9 Hz), 7.14-7.24 (1 H, m), 5.54 (1H, d, J=8.5 Hz), 4.77 (1 H, dd, J=8.5, 4.6 Hz), 4.42-4.52 (1 H, m), 3.94(1 H, br. s.), 3.87-3.91 (1 H, m), 3.71-3.84 (1 H, m), 3.27-3.36 (1 H,m), 3.18-3.26 (2 H, m), 2.95 (3 H, d, J=3.7 Hz), 2.45 (3 H, d, J=4.3Hz), 2.35-2.42 (1 H, m), 2.15-2.23 (1 H, m), 1.84-2.07 (8 H, m). LC(Cond.-IV): R_(t)=2.14 min; LRMS: Anal. Calc. for [M+H]⁺ C₄₆H₄₄N₇O₆:826.32; found: 826.78. HRMS: Anal. Calc. for [M+H]⁺ C₄₆H₄₄N₇O₆:826.3120; found: 826.3116.

Example CB-1

Example CB-1a

A solution of Di-t-butyl dicarbonate (1.35 g, 6.2 mmol) in CH₃CN (2 mL)was added slowly to a suspension of 4-dimethylaminopyridine (24.4 mg,0.2 mmol) and (1S,3S,55)-tert-butyl3-carbamoyl-2-azabicyclo[3.1.0]hexane-2-carboxylate (425 mg, 2 mmol) inCH₃CN (8 mL). The resulting mixture was stirred at ambient temperaturefor 5 h. The solvent was removed under reduced pressure and the residuewas taken up un EtOAc (10 mL) and washed with water (2×10 mL) and brine(10 ml), dried (MgSO₄), filtered and concentrated. The residue waspurified by flash chromatography, eluting with EtOAc/hexanes (10 to60%), to give Example CB-1a as a clear oil (2.46 g, 65% yield). ¹HNMR(CDCl₃, 400 MHz) (mixture of rotamers) δ 5.38 (2 dd, J=11.7, 3.6 Hz, 1H), 3.56 (m, 1 H), 2.71 (m, 1H), 2.04 (m, 1 H), 1.53 (m, 27 H); 1.07 and0.92 (2m, 1 H); 0.71 and 0.63 (2m, 1 H); LC/MS (Cond. CB1): R_(t)=2.31min; Anal. Calc. for [M+H]⁺ C₂₁H₃₅N₂O₇: 427.24; found: 427.

Example CB-1b

A 0.5M aqueous solution of NaOH (0.5 mL, 0.25 mmol) was added to asolution of CB-1a (100 mg, 0.23 mmol) in THF (1.5 mL) and the resultingmixture was stirred at ambient temperature for 16 h. The mixture wasconcentrated under reduced pressure to remove and the remaining aqueousphase was diluted with water (1 mL) and EtOAc (1 mL). The organic phasewas discarded and the remaining aqueous phase was acidified with 1N HClto pH=3 and extracted with EtOAc (3×2 mL). The organic layers werecombined, dried (MgSO4), filtered and concentrated to give Example CB-1bas a clear oil (52.2 mg, quantitative). ¹H NMR (CDCl₃, 400 MHz) (mixtureof rotamers) δ 4.65 (m, 1 H), 3.56 (m, 1 H), 2.56 (m, 1H), 2.39 (m, 1H), 1.55 (m, 9 H); 0.75-0.89 (m, 1 H); LCMS (Cond. CB1) R_(t)=1.33 min,Anal. Calc. for [M+H]⁺ C₁₁H₁₅NO₄; 228.12; found: 228.

Example CB-1c

EEDQ (178 mg, 0.72 mmol) and CB-1b (143 mg, 0.63 mmol) were added to asuspension of JR-D-1b (75.3 mg, 0.3 mmol) in dry CH₂Cl₂ (5 mL). Thereaction mixture was stirred at room temperature for 16 hours. Solventswere removed in vacuo and the crude mixture was purified on a reversephase preparative C-18 column: CB-1c was isolated as a white solid (188mg, 93% yield). LCMS (Cond. CB1)R_(t)=2.00 min, Anal. Calc. forC₃₂H₄₄N₅O₇. [M+H]⁺670.32; found: 670.

Example CB-1

TFA (1 mL) was added to a solution of CB-1c (100 mg, 0.15 mmol) inCH₂Cl₂ and the resulting mixture was stirred at ambient temperature for2 h. Volatiles were removed under reduced pressure and the remainingresidue was taken up in DMF (4 mL) and charged with Cap 130 (58 mg, 0.3mmol), HATU (34.8 mg, 0.3 mmol) and DIEA (0.156 mL, 0.90 mmol). Theresulting mixture was stirred at ambient temperature for 16 h. andpurified by reverse phase preparative HPLC (solvent system: H₂O/MeOH/TFAor H₂O/CH₃CN/TFA) and Example CB1 was obtained as a white TFA salt solid(19.2 mg, 31% yield; ¹HNMR (CDCl₃, 400 MHz) (mixture of rotamers) δ10.36, 10.25 and 10.13 (3 s, 2 H), 8.63 and 8.55 (2 d, J=8.1 Hz, 1 H),8.04 (m, 1 H); 7.81-7.69 (m, 6 H), 7.49-7.30 (m, 9 H), 6.01 and 5.92 (2d, J=6.1, 2 H); 4.57 (m, 2 H); 3.71-3.43 (m, 5 H), 2.55 (m 2 H), 1.83(m, 8 H), 1.62 (m, 2 H), 1.17 (m, 1 H), 0.92-0.70 (m, 2 H), 0.42 (m, 1H); LCMS (Cond. CB1)R_(t)=1.68 min, Anal. Calc. for C₄₇H₄₅N₇O₇.[M+H]⁺819.34; found: 819.

Examples CB-2 to CB-10

Examples CB-2 to CB-10 were prepared from Example CB-1c and 2.0 eq. ofthe appropriate, commercially-available or synthesized carboxylic acidsaccording to the procedure described for the preparation of ExampleCB-1. Purification of the final targets was accomplished using aShimadzu reverse phase preparative HPLC instrument (solvent systems:H₂O/MeOH/TFA or H₂O/ACN/TFA) and the final products were isolated as TFAsalts. The coupling partner (ROH) was obtained from commercial sourcesunless otherwise noted.

Example ROH Analyis CB-2 

LCMS: Anal. Calcd. For [M + H]⁺: C₄₇H₃₈N₇O₅ 780.29; Found: 780. R_(t) =1.86 min Cond. CB1 CB-3 

  Cap 145 LCMS: Anal. Calcd. For [M + H]⁺: C₄₇H₃₆Cl₂N₇O₅ 848.22; Found:848. R_(t) = 2.23 min Cond. CB1 CB-4 

  Cap 151 LCMS: Anal. Calcd. For [M + H]⁺: C₄₉H₄₀Cl₂N₇O₇ 908.24; Found:908.2 R_(t) = 2.35 min Cond. CB1 CB-5 

LCMS: Anal. Calcd. For [M + H]⁺: C₄₃H₄₀N₅O₇ 738.29; Found: 738. R_(t) =1.81 min Cond. CB1 CB-6 

LCMS: Anal. Calcd. For [M + H]⁺: C₄₃H₄₀N₅O₇ 738.29; Found: 738. R_(t) =1.79 min Cond. CB1 CB-7 

LCMS: Anal. Calcd. For [M + H]⁺: C₃₇H₄₀N₅O₇ 666.29; Found: 666. R_(t) =1.53 min Cond. CB1 CB-8 

LCMS: Anal. Calcd. For [M + H]⁺: C₄₅H₄₄N₅O₇ 766.32; Found: 766. R_(t) =1.98 min Cond. CB1 CB-9 

  Cap 1 LCMS: Anal. Calcd. For [M + H]⁺: C₄₇H₅₀N₇O₅ 792.39; Found: 792.R_(t) = 2.17 min Cond. CB1 CB-10

LCMS: Anal. Calcd. For [M + H]⁺: C₄₅H₄₄N₅O₇ 766.32; Found: 766. R_(t) =2.01 min Cond. CB1

Example JG-1

Example JG-1a

A mixture of conc. HNO₃ (8 mL) and conc. H₂SO₄ (20 mL) was added withstirring to a solution of 2,5-diphenyloxazole (20 g, 0.09 mol) in 20 mLconc. H₂SO₄ cooled to 0° C. in an ice/water bath. After addition themixture was allowed to stir at 0° C. for 2 hours and then poured overcrushed ice. The precipitated solid was filtered off, washed with water,and crystallized from ethanol to afford JG-1a as a yellow solid (17.02g, 0.055 mol, 61% yield). ¹H NMR (DMSO-d₆, 300 MHz) δ 8.40 (d, J=3.3 Hz,4H), 8.36 (m, 2H), 8.29 (s, 1H), 8.18 (d, J=8.8 Hz, 2H); LCMS (Cond.JG1): R_(t)=2.41, Anal. Calc. for C₁₅H₁₀N₃O₅ [M+H]⁺312.06; found: 312.

Example JG-1b

JG-1a (9 g, 0.029 mol) was suspended in 110 mL of a 1:1 mixture of ethylacetate/methanol. The suspension was placed under a hydrogen atmosphere(1 atm) in the presence of 1 g of 20% palladium hydroxide on carbon andstirred for 4 hours. HPLC indicates reaction completion. Reactiondiluted with 50 mL of methanol and filtered through a bed of celite. Thefilter cake was washed with 100 mL methanol. The filtrate wasconcentrated under reduced pressure and the residual solid wascrystallized from methanol to afford JG-1b as light brown needles (5.2g, 71% yield). ¹H NMR (DMSO-d₆+D₂O, 300 MHz) δ 7.72 (d, J=8.4 Hz, 2H),7.54 (d, J=8.4 Hz, 2H), 7.40 (s, 1H), 6.83 (d, 8.05 Hz, 2H), 6.69 (d,8.05 Hz, 2H); LCMS (Cond. JG1)R_(t)=0.87 min, Anal. Calc. for C₁₅H₁₄N₃O.[M+H]⁺ 252.11; found: 252.

Example JG-1

EEDQ (0.085 g, 0.35 mmol) and carbobenzyloxy-L-Proline (0.082 g, 0.33mmol) were added to a suspension of JG-1b (0.038 g, 0.15 mmol) in 2 mLdry CH₂Cl₂. The reaction stirred at room temperature for 16 hours.Solvents were removed in vacuo and the crude mixture was purified on areverse phase preparative C-18 column: JG-1 was isolated as a whitesolid (0.015 g, 26% yield). ¹H NMR (DMSO-d₆, 300 MHz) δ 10.22 (1s, 1H)10.07 (1s, 1H), 7.66-7.83, (2m, 2H), 7.55 (dd, J=8.9 Hz×2, 2H),7.49-7.51 (m, 2H), 7.31-7.38 (m, 7H), 7.08-7.21 (2m, 5H), 5.04-5.11 (m,4H), 4.36 (m, 2H), 4.03-4.09 (m, 2H), 3.46 (m, 2H), 2.25 (m, 2H),1.88-1.94 (m, 6H); LCMS (Cond. JG1)R_(t)=2.66 min, Anal. Calc. forC₄₁H₄₀N₅O₂. [M+H]⁺ 714.29; found: 714.

Examples JG-2 to JG-6

Examples JG-2 to JG-6 were prepared from Example JG-1b and 2.0 eq. ofthe appropriate, commercially-available or synthesized carboxylic acidsaccording to the procedure described for the preparation of ExampleJG-1. Purification of the final targets was accomplished using aShimadzu reverse phase preparative HPLC instrument (solvent systems:H₂O/MeOH/TFA or H₂O/ACN/TFA. The coupling partner (ROH) was obtainedfrom commercial sources unless otherwise noted.

JG-2

LCMS: Anal. Calcd. for: C₄₁H₃₉N₅O₇ 713.8; Found: 714 (M + H)⁺. R_(t) =1.09 min Cond. JG1 JG-3

LCMS: Anal. Calcd. for: C₄₁H₃₉N₅O₅ 681.8; Found: 682 (M + H)⁺. R_(t) =2.55 min Cond. JG1 JG-4

LCMS: Anal. Calcd. for: C₄₁H₄₃N₅O₇ 717.83; Found: 718 (M + H)⁺. R_(t) =2.53 min Cond. JG1 JG-5

LCMS: Anal. Calcd. for: C₄₁H₄₃N₅O₇ 717.83; Found: 718 (M + H)⁺. R_(t) =2.49 min Cond. JG1 JG-6

LCMS: Anal. Calcd. for: C₄H₄₃N₅O₅ 709.85; Found: 710 (M + H)⁺. R_(t) =2.83 min Cond. JG1

Example JG-7

Example JG-7a

EEDQ (2.14 g, 8.6 mmol) and tBoc-L-Proline (1.77 g, 8.3 mmol) were addedto a suspension of JG-1b (0.9 g, 3.6 mmol) in 14 mL dry CH₂Cl₂. Thereaction stirred at room temperature for 4 hours. The solution volumewas reduced to 3 mL under reduced pressure and pentane was added to theresulting concentrate in order to precipitate solid. Solid was collectedby vacuum filtration and dried under vacuum to yield JG-7a as a tansolid, 1.21 g (52% yield). ¹H NMR (DMSO-d₆, 300 MHz) δ 10.26 (s, 1H),10.17 (s, 1H), 8.02 (m, 2H), 7.65-7.80 (m, 7H), 4.22 (m, 2H), 2.21 (m,2H), 1.89 (m, 6H), 1.40+1.27 (2s, 18H); LCMS (Cond. JG1)R_(t)=2.61 min,Anal. Calc. for C₃₅H₄₄N₅O₂. [M+H]⁺646.3; found: 646.

Example JG-7b

To a solution of JG-7a (0.6 g, 0.90 mmol) in 2 mL CH₂Cl₂ was added 8 mLof a 1:1 solution of trifluoroacetic acid and CH₂Cl₂. After stirring atroom temperature for 4 hours, solvents were removed in vacuo leaving ared oil. Pentane was added to the residue and once again placed undervacuum to remove solvent. Residual oil was pumped dry and JG-7b isobtained as a crunchy brown solid (0.68 g) which is of sufficient purityfor use in subsequent reactions. ¹H NMR (DMSO-d₆, 500 MHz) δ 10.86 (s,1H), 10.77 (s, 1H), 9.48 (br s, 2H), 8.08 (t, J=7.9 Hz×2, 2H), 7.73-7.84(m, 7H) 4.16-4.38 (m, 2H), 4.31 (m, 4H), 2.40 (m, 2H), 2.05-1.93 (m,6H); LCMS (Cond. JG1)R_(t)=2.61 min, Anal. Calc. for C₂₅H₂₈N₅O₃.[M+H]⁺446.5; found: 446.

Example JG-7

Triethylamine (0.125 mL, 0.9 mmol) and cyclopropanecarbonyl chloride(0.034 mL, 0.4 mmol) were added to a solution of 0.1 g JG-7b in 1 mL dryCH₂Cl₂. The mixture was stirred at 25° C. for 1 hour and monitored byHPLC. The reaction was diluted with 5 mL CH₂Cl₂ and washed with water,and brine. The organic layer was dried over MgSO₄ and evaporated todryness. Crude material was purified on a reverse phase preparative C-18column: JG-7 was isolated as a yellow solid (0.017 g, 20% yield). ¹H NMR(DMSO-d₆, 300 MHz) δ 10.29 (s, 1H), 10.17 (s, 1H), 8.00 (m, 2H),7.68-7.90 (m, 7H), 4.74-4.44 (m, 2H), 2.21 (m, 2H), 3.48-3.79 (2m, 4H),2.16 (m, 2H) 1.84-2.05 (3m, 8H) 0.66-0.76 (m, 8H); LCMS (Cond.JG2)R_(t)=2.75 min, Anal. Calc. for C₃₃H₃₆N₅O₅; [M+H]⁺ 582.6; found:582.

Examples JG-8 to JG-10

Examples JG-8 to JG-10 were prepared from Example JG-7b and 2.0 eq. ofthe appropriate, commercially-available or synthesized carboxylic acidsaccording to the procedure described for the preparation of ExampleJG-7. Purification of the final targets was accomplished using aShimadzu reverse phase preparative HPLC instrument (solvent systems:H₂O/MeOH/TFA or H₂O/ACN/TFA. The coupling partner (ROH) was obtainedfrom commercial sources unless otherwise noted.

JG-8 

LCMS: Anal. Calcd. for: C₃₁H₃₅N₅O₅ 557.6; Found: 558 (M + H)⁺. R_(t) =2.65 min Cond. JG2 JG-9 

LCMS: Anal. Calcd. for: C₃₅H₃₉N₅O₅ 609.7; Found: 610 (M + H)⁺. R_(t) =3.04 min Cond. JG2 JG-10

  · 2TFA LCMS: Anal. Calcd. for: C₃₇H₃₃N₇O₅ 655.7; Found: 656 (M + H)⁺.R_(t) = 2.12 min Cond. JG2 JG-11

LCMS: Anal. Calcd. for: C₂₉H₃₁N₅O₅ 529.6; Found: 530 (M + H)⁺. R_(t) =2.03 min Cond. JG2

The following examples were synthesized by parallel synthesis performingeach step in 21 mL scintillation vials without purification until thethird and final step.

Example JG-12

EEDQ (0.061 g, 0.25 mmol) and Fmoc-Val-OH (0.084 g, 0.25 mmol) wereadded to a solution of JG-1b (0.025 g, 0.099 mmol) in 3 mL dry CH₂Cl₂ ina 21 mL scintillation vial. The reaction stirred at room temperature for18 hours. Piperidine (0.25 mL) was added to the vial and the mixture wasstirred at room temperature for an additional 6 hours. Solvents wereremoved in vacuo and the resulting residue was re-dissolved in 3 ml dryCH₂Cl₂. Triethylamine (0.050 mL, 0.30 mmol) and phenacetyl chloride(0.039 mL, 0.30 mmol) were added to the vial and stirred at roomtemperature for 2 hours. Solvents were removed in vacuo and the crudemixture was purified on a reverse phase preparative C-18 column: JG-12was isolated as a white solid (0.0038 g, 5.6% yield). LCMS (Cond. JG1)R_(t)=2.76 min, Anal. Calc. for C₄₁H₄₅N₅O₅; [M+H]⁺ 686.8; found: 686.

Examples JG-13 to JG-18

Examples JG-13 to JG-18 were prepared from Example JG-1b and 2.0 eq. ofthe appropriate, commercially-available or synthesized carboxylic acidsaccording to the procedure described for the preparation of ExampleJG-12. Purification of the final targets was accomplished using aShimadzu reverse phase preparative HPLC instrument (solvent systems:H₂O/MeOH/TFA or H₂O/ACN/TFA. The coupling partner (ROH) was obtainedfrom commercial sources unless otherwise noted.

JG-13

LCMS: Anal. Calcd. for: C₄₁H₄₃N₅O₅S₂ 749.9; Found: 750.2 (M + H)⁺. R_(t)= 2.71 min Cond. JG1 JG-14

LCMS: Anal. Calcd. for: C₃₉H₃₉N₅O₅S₂ 721.9; Found: 722 (M + H)⁺. R_(t) =2.65 min Cond. JG1 JG-15

LCMS: Anal. Calcd. for: C₄₁H₄₃N₅O₇ 717.83; Found: 718 (M + H)⁺. R_(t) =3.89 min Cond. JG3 JG-16

LCMS: Anal. Calcd. for: C₄₅H₅₁N₅O₇ 773.9; Found: 775 (M + H)⁺. R_(t) =3.15 min Cond. JG3 JG-17

LCMS: Anal. Calcd. for: C₄₃H₄₇N₅O₅ 713.88; Found: 714 (M + H)⁺. R_(t) =3.02 min Cond. JG1 JG-18

LCMS: Anal. Calcd. for: C₃₉H₃₅N₅O₅ 653.74; Found: 654 (M + H)⁺. R_(t) =2.66 min Cond. JG1

Example JG-19

HATU (48 mg, 0.128 mmol)) was added in one portion to a stirred solutionof JG-7b (30 mg, 0.058 mmol), diisopropylethylamine (0.045 ml, 0.350mmol) and (S)-(+)-methoxyphenyl acetic acid (21 mg, 0.128 mmol) inanhydrous dimethylformamide (1.5 mL) at room temperature. The mixturewas stirred for 16 h. Solvents were removed in vacuo and residue waspurified by preparatory HPLC on C₁₈-reverse phase to afford JG-19 as ayellow solid, 12.8 mg (30% yield). LRMS: Anal. Calc. for [M+H]⁺C₄₃H₄₄N₅O_(7:) 742.8; found 742.5.

Examples JG-20 to JG-30

Examples JG-20 to JG-30 were prepared from Example JG-7b and 2.0 eq. ofthe appropriate, commercially-available or synthesized carboxylic acidsaccording to the procedure described for the preparation of ExampleJG-19. Purification of the final targets was accomplished using aShimadzu reverse phase preparative HPLC instrument (solvent systems:H₂O/MeOH/TFA or H₂O/ACN/TFA. The coupling partner (ROH) was obtainedfrom commercial sources unless otherwise noted.

JG- 20

LCMS: Anal. Calcd. for: C₄₁H₃₉N₅O₇ 713.8; Found: 714.2 (M + H)⁺. R_(t) =2.02 min Cond. JG1 JG- 21

HRMS: Anal. Calcd. for: C₄₅H₄₄N₅O₉ 798.3139; Found: 798.3173 (M + H)⁺.JG- 22

LCMS: Anal. Calcd. for: C₄₃H₄₃N₅O₇ 741.8; Found: 742.3 (M + H)⁺. R_(t) =2.60 min Cond. JG1 JG- 23

LCMS: Anal. Calcd. for: C₄₁H₃₉N₅O₇ 713.8; Found: 714.2 (M + H)⁺. R_(t) =1.99 min Cond. JG1 JG- 24

HRMS: Anal. Calcd. for: C₄₅H₄₄N₅O₉ 798.3139; Found: 798.3114 (M + H)⁺.JG- 25

LCMS: Anal. Calcd. for: C₄₃H₄₃N₅O₇ 741.9; Found: 742.4 (M + H)⁺. R_(t) =2.37 min Cond. JG1 JG- 26

LCMS: Anal. Calcd. for: C₄₁H₃₇Cl₂N₅O₇ 782.6; Found: 783.3 (M + H)⁺.R_(t) = 2.42 min Cond. JG1 JG- 27

LCMS: Anal. Calcd. for: C₄₁H₃₅N₅O₇ 709.7; Found: 710.2 (M + H)⁺. R_(t) =2.90 min Cond. JG1 JG- 28

LCMS: Anal. Calcd. for: C₄₃H₃₅N₅O₇ 733.8; Found: 734.2 (M + H)⁺. R_(t) =2.95 min Cond. JG1 JG- 29

LCMS: Anal. Calcd. for: C₄₁H₃₃N₇O₅S₂ 767.9; Found: 768.3 (M + H)⁺. R_(t)= 2.45 min Cond. JG4 JG- 30

LCMS: Anal. Calcd. for: C₄₁H₃₃N₇O₇ 735.7; Found: 736.2 (M + H)⁺. R_(t) =1.82 min Cond. JG4

Example JG-31

HATU (45 mg, 0.119 mmol)) was added in one portion to a stirred solutionof OL-31b (30 mg, 0.054 mmol), diisopropylethylamine (0.060 ml, 0.324mmol) and benzoyl formic acid (18 mg, 0.119 mmol) in anhydrousdimethylformamide (1.5 mL) at room temperature. The mixture was stirredfor 16 h. Solvents were removed in vacuo and residue was purified bypreparatory HPLC on C₁₈-reverse phase to afford JG-31 as atrifluoroacetic acid salt, 11.3 mg (25% yield). ¹H NMR (500 MHz,DMSO-d₆) δ ppm 10.40 (2 H, br. s.), 8.06 (1 H, s), 8.05 (2 H, d, J=1.2Hz), 7.87-7.94 (1 H, m), 7.76-7.85 (4 H, m), 7.70-7.75 (3 H, m),7.63-7.69 (4 H, m), 7.53 (1 H, t, J=7.8 Hz), 7.36 (1 H, d, J=8.5 Hz),7.09 (1 H, s), 4.58-4.71 (2 H, m), 3.69 (2 H, br. s.), 3.35-3.55 (4 H,m), 2.28-2.48 (2 H, m), 1.87-1.98 (6 H, m); LCMS (Cond. JG4)R_(t)=2.20min, Anal. Calc. for [M+H]⁺ C₄₁H₃₇N₆O₆:709.8; found 709.3.

Examples JG-32 to JG-41

Examples JG-32 to JG-41 were prepared from Example OL31b and 2.0 eq. ofthe appropriate, commercially-available or synthesized carboxylic acidsaccording to the procedure described for the preparation of ExampleJG-31. Purification of the final targets was accomplished using aShimadzu reverse phase preparative HPLC instrument (solvent systems:H₂O/MeOH/TFA or H₂O/ACN/TFA) and the final products were isolated as theTFA salts. The coupling partner (ROH) was obtained from commercialsources unless otherwise noted.

JG-32

  TFA LCMS: Anal. Calcd. for: C₄₁H₃₉N₅O₇ 712.8; Found: 713.2 (M + H)⁺.R_(t) = 1.84 min Cond. JG1 JG-33

  TFA LCMS: Anal. Calcd. for: C₄₁H₃₉N₅O₇ 712.8; Found: 713.3 (M + H)⁺.R_(t) = 1.86 min Cond. JG1 JG-34

  TFA HRMS: Anal. Calcd. for: C₄₅H₄₅N₆O₈ 797.3294; Found: 797.3286 (M +H)⁺. JG-35

  TFA HRMS: Anal. Calcd. for: C₄₅H₄₅N₆O₈ 797.3294; Found: 797.3276 (M +H)⁺. JG-36

  TFA LCMS: Anal. Calcd. for: C₄₁H₃₈Cl₂N₆O₆ 781.7; Found: 782.4 (M +H)⁺. R_(t) = 1.97 min Cond. JG4 JG-37

  TFA LCMS: Anal. Calcd. for: C₄₃H₄₄N₆O₆ 740.8; Found: 741.2 (M + H)⁺.R_(t) = 1.94 min Cond. JG4 JG-38

  TFA LCMS: Anal. Calcd. for: C₄₃H₄₄N₆O₆ 740.8; Found: 741.3 (M + H)⁺.R_(t) = 1.96 min Cond. JG4 JG-39

  TFA LCMS: Anal. Calcd. for: C₄₃H₄₄N₆O₆ 740.8; Found: 741.2 (M + H)⁺.R_(t) = 2.11 min Cond. JG4 JG-40

  TFA LCMS: Anal. Calcd. for: C₄₃H₃₆N₆O₆ 732.8; Found: 733.5 (M + H)⁺.R_(t) = 2.09 min Cond. JG4 JG-41

  TFA LCMS: Anal. Calcd. for: C₄₁H₃₄N₈O₄S₂ 766.9; Found: 767.8 (M + H)⁺.R_(t) = 2.24 min Cond. JG4

Example JG-42

Prepared according to the procedure described for Example JG-31. Thisafforded Example JG-42 as a trifluoroacetic acid salt, 8.7 mg (29%yield). ¹H NMR (300 MHz, DMSO-d₆) δ ppm 10.53 (2 H, s), 9.27 (1 H, br.s.), 8.03 (2 H, d, J=7.3 Hz), 7.89 (1 H, d, J=7.3 Hz), 7.70-7.81 (5 H,m), 7.63 (4 H, t, J=7.5 Hz), 7.35-7.56 (6 H, m), 7.23-7.34 (1 H, m),4.64 (2H, d, J=4.0 Hz), 3.68 (2 H, br. s.), 3.33-3.55 (4 H, m),2.21-2.43 (2 H, m), 1.81-2.11 (6 H, m); LCMS (Cond. JG3)R_(t)=2.76 min,Anal. Calc. for [M+H]⁺ C₄₁H₃₇N₆O₆:709.8; found 709.4.

Examples JG-43 to JG-52

Examples JG-43 to JG-52 were prepared from Example JG-31 and 2.0 eq. ofthe appropriate, commercially-available or synthesized carboxylic acidsaccording to the procedure described for the preparation of ExampleJG-42. Purification of the final targets was accomplished using aShimadzu reverse phase preparative HPLC instrument (solvent systems:H₂O/MeOH/TFA or H₂O/ACN/TFA) and the final products were isolated as TFAsalts. The coupling partner (ROH) was obtained from commercial sourcesunless otherwise noted.

JG-43

  TFA LCMS: Anal. Calcd. for: C₄₁H₄₀N₆O₆ 712.8; Found:713.3 (M + H)⁺.R_(t) = 2.45 min Cond. JG3 JG-44

  TFA LCMS: Anal. Calcd. for: C₄₁H₄₀N₆O₆ 712.8; Found:713.4 (M + H)⁺.R_(t) = 2.49 min Cond. JG3 JG-45

  TFA LCMS: Anal. Calcd. for: C₄₃H₄₄N₆O₆ 740.8; Found:741.5 (M + H)⁺.R_(t) = 2.69 min Cond. JG3 JG-46

  TFA LCMS: Anal. Calcd. for: C₄₃H₄₄N₆O₆ 740.8; Found:741.4 (M + H)⁺.R_(t) = 2.95 min Cond. JG3 JG-47

  TFA LCMS: Anal. Calcd. for: C₄₃H₄₄N₆O₆ 740.8; Found:741.4 (M + H)⁺.R_(t) = 2.84 min Cond. JG3 JG-48

  · 3TFA LCMS: Anal. Calcd. for: C₄₅H₃₈N₈O₄ 754.8; Found:755.5 (M + H)⁺.R_(t) = 1.98 min Cond. JG4 JG-49

  · 3TFA LCMS: Anal. Calcd. for: C₄₅H₃₆Cl₂N₈O₄ 823.7; Found:824.9 (M +H)⁺. R_(t) = 2.39 min Cond. JG3 JG-50

  · 3TFA LCMS: Anal. Calcd. for: C₄₇H₄₀Cl₂N₈O₆ 883.8; Found:884.5 (M +H)⁺. R_(t) = 3.36 min Cond. JG3 JG-51

  TFA LCMS: Anal. Calcd. for: C₄₃H₃₆N₆O₆ 732.8; Found:733.4 (M + H)⁺.R_(t) = 2.81 min Cond. JG3 JG-52

  TFA LCMS: Anal. Calcd. for: C₄₃H₃₆N₆O₆ 732.8; Found:733.4 (M + H)⁺.R_(t) = 2.67 min Cond. JG3

Example JG-53

Example JG-53a

Sec-butyllithium (107 mL, 150 mmol) was added drop-wise to a solution offuran (4.4 mL, 60 mmol) and tetramethylethylenediamine (22.60 mL, 150mmol) in 150 mL hexanes at 0° C. After 1 hour, the reaction mixture waswarmed to room temperature and stirred for four hours. The mixture wascooled to 0° C. and trimethyltin chloride (32.3 g, 162 mmol) in 50 mLhexanes was added drop-wise. The mixture was warmed to room temperatureand stirred overnight (17 hours). Saturated ammonium chloride (150 mL)was added and the layers separated. Organic phase was washed withaqueous copper sulfate, dried over anhydrous sodium sulfate andconcentrated under reduced pressure to give Example JG-53a as a orangeoil. The material was used for the next step without furtherpurification. ¹H NMR (500 MHz, DMSO-d₆) ppm 6.65 (s, 2 H), 0.30 (s, 18H).

Example JG-53b

Example JG-53a (2.00 g, 5.10 mmol) was added to a suspension ofPd(PPh₃)₂Cl₂ (0.033 g, 0.180 mmol), and 4-nitrobenzene (2.60 g, 10.5mmol) in 75 mL THF and heated at reflux temperature for 20 hours. Uponcooling, an orange solid precipitated. The suspension was diluted with100 mL hexanes and the solid was collected by vacuum filtration. Thecollected solid was washed three times with hexanes and dried. ExampleJG-53b was isolated as an orange solid (1.28 g, 81%). ¹H NMR(DMSO-_(d6), 300 MHz) δ ppm 8.33 (4 H, d, J=8.4 Hz), 8.15 (4 H, d, J=8.8Hz), 7.56 (2 H, s); LRMS, Anal. Calc. for C₁₆H₁₀N₂O₅ [M+H]⁺311.20;found: 311.

Example JG-53c

Example JG-53b (1.20 g. 3.90 mmol) was suspended in 200 mL of a 1:1mixture of ethyl acetate/methanol. The suspension was placed under ahydrogen atmosphere (1 atm) in the presence of 0.10 g of 20% palladiumhydroxide on carbon and stirred for 4 hours. HPLC indicated the reactionwas completed, so the mixture was diluted with 50 mL of methanol andfiltered through a bed of celite. The filter cake was washed with 100 mLmethanol and the filtrate was concentrated under reduced pressure andthe residual solid corresponding to Example JG-53c was collected aslight brown needles (0.75 g, 77% yield). ¹H NMR (DMSO-d₆, 300 MHz) δ7.37 (m, 8H), 6.94 (s, 2H); LRMS Anal. Calc. for C₁₆H₁₄N₂O [M+H]⁺251.20;found: 251.

Example JG-53d

EEDQ (1.47 g, 5.96 mmol) and Boc-L-Proline (1.28 g, 5.96 mmol) wereadded to a suspension of Example JG-53c (0.71 g, 2.84 mmol) in 15 mL dryCH₂Cl₂. The reaction stirred at room temperature for 16 hours. Thereaction was concentrated to 5 mL in vacuo. Pentane was added toprecipitate a white solid, which was collected by vacuum filtration.Example JG-53d was isolated as a white solid (1.42 g, 77% yield). Thematerial was used for the next step without further purification. LRMS:Anal. Calc. for C₃₆H₄₄N₄O₇; [M+H]⁺645.50; found: 645.

Example JG-53e

4.0M HCl in dioxane (2.20 mL, 8.68 mmol) was added to a suspension ofExample JG-53d (1.40, 2.17 mmol) in 4.0 mL of dioxane and stirred for 4hours. The volatile component was removed in vacuo and the HCl salt ofExample JG-53e was isolated as a tan solid (1.12 g, 98% yield). Materialwas used for next steps without further purification. ¹H NMR (DMSO-d₆,300 MHz δ ppm 10.99 (2 H, s), 9.88 (2 H, br. s.), 8.69 (2 H, br. s.),7.77-7.85 (4 H, m), 7.67-7.76 (4 H, m), 7.00 (2 H, s), 4.39 (2 H, d,J=6.6 Hz), 3.27 (4 H, br. s.), 2.35-2.47 (2 H, m), 1.86-2.06 (6 H, m)LRMS Anal. Calcd. for [M+H]⁺ C₂₆H₂₈N₄O₃: 445.22; found 445.

Example JG-53

HATU (30.0 mg, 0.086 mmol) was added to a mixture of Example JG-53e(20.0 mg, 0.039 mmol), (R)-2-phenylpropanoic acid (18.0 mg, 0.078 mmol)and DIEA (41 μL, 0.23 mmol) in DMF (1.5 mL), and the mixture was stirredfor 3 h. The volatile component was removed in vacuo and the residue waspurified by reverse phase HPLC (MeOH/H₂O/TFA) to afford the ExampleJG-53 as an off-white solid (10.1 mg) ¹H NMR (DMSO-d₆, 500 MHz) δ ppm10.14 (2 H, s), 7.73-7.83 (4 H, m), 7.66-7.73 (4 H, m), 7.29-7.39 (7 H,m), 7.26 (3 H, d, J=6.7 Hz), 6.97 (2 H, s), 4.41 (2 H, dd, J=8.2, 3.7Hz), 4.01 (2 H, d, J=6.7 Hz), 3.80 (2 H, br. s.), 3.22 (2 H, d, J=9.8Hz), 2.03 (4 H, br. s.), 1.89 (3 H, br. s.), 1.77 (2 H, br. s.), 1.31 (6H, d, J=6.7 Hz). LRMS: Anal. Calcd. for [M+H]⁺ C₄₄H₄₅N₄O₅: 709.33;found: 709. HRMS: Anal. Calcd. for [M+H]⁺ C₄₄H₄₅N₄O₅: 709.3388; found709.3390.

Example JG-54 to JG-70

Examples 54-70 were prepared from intermediate Example JG-53c or ExampleJG-53e and appropriate acids by employing EEDQ or HATU couplingconditions and a reverse phase HPLC (H₂O/MeOH/TFA) purification system.

JG- 54

LRMS: Anal. Calcd. For (M + H)⁺ C₄₂H₄₀N₄O₇: 712.81 found: 713.13 JG- 55

LRMS: Anal. Calcd. For (M + H)⁺ C₃₀H₃₂N₄O₅: 528.61 found: 529.13 JG- 56

LRMS: Anal. Calcd. For (M + H)⁺ C₄₀H₄₀N₄O₇: 712.81 found: 713.72 HRMS:Anal. Calcd. For (M + H)⁺ C₄₀H₄₁N₄O₇: 713.2975 found: 713.3010 JG- 57

LRMS: Anal. Calcd. For (M + H)⁺ C₄₂H₄₀N₄O₇: 712.81 found: 713.72 HRMS:Anal. Calcd. For (M + H)⁺ C₄₀H₄₁N₄O₇: 713.2975 found: 713.2836 JG- 58

LRMS: Anal. Calcd. For (M + H)⁺ C₄₄H₄₄N₄O₇: 740.86 found: 741.20 HRMS:Anal. Calcd. For (M + H)⁺ C₄₄H₄₅N₄O₇: 741.3131 found: 741.3710 JG- 59

LRMS: Anal. Calcd. For (M + H)⁺ C₄₄H₄₄N₄O₇: 740.32 found: 741.43 HRMS:Anal. Calcd. For (M + H)⁺ C₄₄H₄₅N₄O₇: 741.3288 found: 741.3269 JG- 60

LRMS: Anal. Calcd. For (M + H)⁺ C₄₈H₄₀Cl₂N₆O₇: 883.80 found: 883.74HRMS: Anal. Calcd. For (M + H)⁺ C₄₈H₄₁Cl₂N₆O₇: 883.2413 found: 883.2426JG- 61

LRMS: Anal. Calcd. For (M + H)⁺ C₄₆H₃₆Cl₂N₆O₅: 823.74 found: 823.69HRMS: Anal. Calcd. For (M + H)⁺ C₄₆H₃₇Cl₂N₆O₅: 823.2202 found: 823.2224JG- 62

LRMS: Anal. Calcd. For (M + H)⁺ C₄₆H₃₈N₆O₅: 754.85 found: 755.72 HRMS:Anal. Calcd. For (M + H)⁺ C₄₆H₃₉N₆O₅: 755.2982 found: 755.2985 JG- 63

LRMS: Anal. Calcd. For (M + H)⁺ C₄₆H₄₀N₆O₅: 766.95 found: 767.82 HRMS:Anal. Calcd. For (M + H)⁺ C₄₆H₄₁N₆O₅: 767.3921 found: 767.3953

Example JG-64

HATU (65.0 mg, 0.14 mmol) was added to a mixture of Example JG-53a (40.0mg, 0.07 mmol), R-(−)-Mandelic acid (11.8 mg, 0.07 mmol, Cap-151 (18.4mg, 0.07 mmol), and DIEA (82 μL, 0.42 mmol) in DMF (1.5 mL), and themixture was stirred for 3 h. The volatile component was removed in vacuoand the residue was purified with a reverse phase HPLC (MeOH/H₂O/TFA) toafford Example JG-64 as an off-white solid (6.7 mg) LRMS: Anal. Calcd.for [M+H]⁺ C₄₅H₄₁ClN₅O₂: 798.33; found: 798. HRMS: Anal. Calcd. for[M+H]⁺ C₄₅H₄₁ClN₅O₂: 798.2594; found 798.2547. The symmetrical analogswere also separated and they were described previously.

JG-65

LRMS: Anal. Calcd. for (M + H)⁺ C₄₇H₄₅ClN₆O₆: 825.37 found: 825.77 HRMS:Anal. Calcd. for (M + H)⁺ C₄₇H₄₆ClN₆O₆: 825.3167 found: 825.3002 JG-66

LRMS: Anal. Calcd. For (M + H)⁺ C₄₄H₄₅N₅O₆: 739.88 found: 740.43 HRMS:Anal. Calcd. For (M + H)⁺ C₄₄H₄₆N₅O₆: 740.3448 found: 740.7561 JG-67

LRMS: Anal. Calcd. for (M + H)⁺ C₄₇H₄₃ClN₆O₇: 839.36 found: 839.81 HRMS:Anal. Calcd. for (M + H)⁺ C₄₇H₄₄ClN₆O₇: 839.2960 found: 839.2930 JG-68

LRMS: Anal. Calcd. for (M + H)⁺ C₄₅H₄₀ClN₅O₇: 798.30 found: 798.76 HRMS:Anal. Calcd. for (M + H)⁺ C₄₅H₄₁ClN₅O₇: 798.2694 found: 798.2671 JG-69

LRMS: Anal. Calcd. For (M + H)⁺ C₄₆H₄₄N₄O₉: 796.88 found: 797.53 HRMS:Anal. Calcd. For (M + H)⁺ C₄₆H₄₅N₄O₉: 797.3186 found: 797.3220 JG-70

LRMS: Anal. Calcd. For (M + H)⁺ C₄₆H₄₄N₄O₉: 796.88 found: 797.00 HRMS:Anal. Calcd. For (M + H)⁺ C₄₆H₄₅N₄O₉: 797.3186 found: 797.3148

Example FY-1

Example FY-1a

Prepared according to the procedure described for Example OL-1c from1-methyl-3,5-bis(4-nitrophenyl)-1H-pyrazole, which was obtained fromcommercially available 1-methyl-3,5-diphenyl-1H-pyrazole according tothe procedure described for Example JR-D-1a. This afforded Example FY-1a(0.2831 g, 99% yield) as an off-white solid. ¹H NMR (500 MHz, DMSO-d₆) δppm 7.45 (2 H, d, J=8.9 Hz), 7.18 (2 H, d, J=8.5 Hz), 6.65 (2 H, d,J=8.5 Hz), 6.57 (2 H, d, J=8.5 Hz), 6.42 (1 H, s), 5.24 (4 H, br. s.),3.72-3.79 (3 H, m); LC/MS (Cond. 1V): R_(t)=0.197 min; Anal. Calc. for[M+H]⁺ C₁₆H₁₇N₄: 265.15; found: 265.31.

Example FY-1

Prepared according to the procedure described for Example OL-1d. Thisafforded Example FY-1 (0.0872 g, 83% yield) as a white powder. ¹H NMR(500 MHz, <DMSO>) δ ppm 9.88-10.47 (2 H, m), 7.42-7.91 (8 H, m),7.08-7.39 (10 H, m), 6.67-6.92 (1 H, m), 4.31-4.80 (2 H, m), 3.23-3.99(11 H, m), 1.71-2.43 (8 H, m). LC/MS (Cond. 1V): R_(t)=1.683 min; Anal.Calc. for [M+H]⁺ C₄₂H₄₃N₆O₄: 695.34; found: 695.40.

Example FY-2

Prepared according to the procedure described for Example OL-1d. Thisafforded Example FY-2 (0.0547 g, 67% yield) as a white powder. ¹H NMR(500 MHz, <DMSO>) δ ppm 9.92-10.38 (2 H, m), 7.70-7.84 (4 H, m),7.59-7.67 (2 H, m), 7.46-7.57 (2 H, m), 6.74-6.84 (1 H, m), 4.32-4.61 (2H, m), 3.82-3.93 (3 H, m), 3.32-3.72 (4 H, m), 1.70-2.40 (14 H, m);LC/MS (Cond. 1V): R_(t)=1.28 min; Anal. Calc. for [M+H]⁺ C₃₀H₃₅N₆O₄:543.27; found: 543.42.

Example FY-3

Prepared according to the procedure described for Example OL-1d. Thisafforded Example FY-3 (0.0996 g, 20% yield) as a white powder ¹H NMR(500 MHz, <DMSO>) δ ppm 10.19-10.28 (1 H, m), 10.09 (1 H, d, J=9.2 Hz),7.00-7.93 (18 H, m), 6.80 (1 H, t, J=6.4 Hz), 5.03-5.17 (3 H, m),4.91-5.02 (1 H, m), 4.26-4.47 (2 H, m), 3.77-3.93 (3 H, m), 3.33-3.63 (4H, m), 2.12-2.39 (2 H, m), 1.77-2.05 (6 H, m); LC/MS (Cond. 1V):R_(t)=1.77 min; Anal. Calc. for [M+H]⁺ C₄₂H₄₃N₆O₆: 727.33; found:727.36.

Example FY-4

Prepared according to the procedure described for Example OL-1d. Thisafforded Example FY-4 (0.0185 g, 14% yield) as a white powder. ¹H NMR(500 MHz, <DMSO>) δ ppm 9.89-10.39 (2 H, m), 7.44-7.83 (8 H, m),6.68-6.85 (1 H, m), 4.34-4.82 (2 H, m), 3.86 (3 H, s), 3.65-3.83 (3 H,m), 3.37-3.58 (1 H, m), 1.44-2.41 (10 H, m), 0.56-0.85 (8 H, m); LC/MS(Cond. 1V): R_(t)=1.43 min; Anal. Calc. for [M+H]⁺ C₃₄H₃₉N₆O₄: 595.31;found: 595.36.

Example FY-5

Example FY-5a

To a stirred solution of Example JG-1b (0.2 g, 0.796 mmol) and charcoal(0.01 g, 0.05 wt %) in EtOAc (8 mL) at ambient temperature was addeddiphosgene (0.205 g, 1.035 mmol). The reaction was heated to reflux fortwo hours and concentrated in vacuo to give Example FY-5a (0.241 g,100%) as a green powder. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 7.95-8.17 (2 H,m), 7.57-7.93 (4 H, m), 7.37-7.51 (1 H, m), 7.22-7.35 (2 H, m).

Example FY-5b

To a stirred solution of (R)-3-Aminopyrrolidine (1.2 g, 11.61 mmol) inMeOH (10 mL) at −5° C. was added 1N HCl (11.6 mL, 11.61 mmol) followedby di-t-butyldicarbonate (2.79 g, 12.78 mmol) in MeOH (10 mL). Two hourslater, it was concentrated in vacuo. To the residue was added 1N HCl(2.32 mL) and the aqueous mixture was washed with methylene chloride (10mL). The aqueous layer was basified by addition of potassium carbonate(1.93 g, 13.96 mmol) and then extracted with methylene chloride (30mL×2). The combined extracts were concentrated in vacuo to give ExampleFY-5b (1.91 g, 88%) as colorless oil. ¹H NMR (500 MHz, DMSO-d₆) δ ppm3.36-3.45 (1 H, m), 3.27-3.36 (2 H, m), 3.13-3.25 (1 H, m), 2.87 (1 H,dd, J=10.5, 4.7 Hz), 1.77-1.95 (1 H, m), 1.63 (2 H, br. s.), 1.47-1.59(1 H, m), 1.40 (9 H, s).

Example FY-5c

To a stirred solution of Example FY-5a (0.04 g, 0.139 mmol) in CH₂Cl₂ (1mL) at ambient temperature was added Example FY-5b (0.059 g, 0.316 mmol)in CH₂Cl₂ (1 mL). After one hour, the mixture was filtered andconcentrated in vacuo to give Example FY-5c (0.02 g, 22%) as whitesolid. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.71 (1 H, br. s.), 8.58 (1 H,br. s.), 7.94 (2 H, d, J=8.5 Hz), 7.69 (2 H, d, J=8.5 Hz), 7.61 (1 H,s), 7.57 (2 H, d, J=8.5 Hz), 7.52 (2 H, d, J=8.5 Hz), 6.61 (1 H, br.s.), 6.55 (1 H, br. s.), 4.18 (2 H, br. s.), 3.49 (2 H, br. s.), 3.34 (4H, br. s.), 3.13 (2 H, br. s.), 2.07 (2 H, br. s.), 1.81 (2 H, br. s.),1.43 (18 H, s); LC/MS (Cond. 1V): R_(t)=1.90 min; Anal. Calc. for [M+H]⁺C₃₅H₄₆N₇O₇: 676.35; found: 676.52.

Example FY-5d

To Example FY-5c (0.178 g, 0.2631 mmol) was added 4N HCl/dioxane (15 ml)and stirred for three hours at ambient temperature. The reaction mixturewas concentrated in vacuo to give Example FY-5d (0.1901 g, 100%) asyellow solid. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 9.26 (1 H, s), 9.13-9.22(1 H, m), 9.11 (1 H, s), 9.04 (1 H, br. s.), 7.90-7.97 (2 H, m), 7.70 (2H, d, J=8.5 Hz), 7.58-7.63 (3 H, m), 7.52-7.57 (2 H, m), 7.02 (1 H, d,J=6.1 Hz), 6.96 (1 H, d, J=5.8 Hz), 4.30 (2 H, br. s.), 3.39 (2 H, dd,J=4.6, 2.4 Hz), 3.28-3.35 (2 H, m), 3.17-3.28 (2 H, m), 3.00-3.12 (2 H,m), 2.15-2.26 (2 H, m), 1.86 (2 H, dd, J=13.1, 6.4 Hz); LC/MS (Cond.1V): R_(t)=1.03 min; Anal. Calc. for [M+H]⁺ C₂₅H₃₀N₇O₃: 476.24; found:476.64.

Example FY-5

To a stirred solution of Example FY-5d (0.025 g, 0.0046 mmol) in DMF (1mL) at ambient temperature was added Hunig's base (0.048 mL, 0.0276mmol), (R)-mandelic acid (0.021 g, 0.0138 mmol), and HATU (0.0536 g,0.0138) sequentially. The reaction was allowed to stir overnight atwhich point methanol (1 ml) was added and the reaction was loadeddirectly onto preparative HPLC. Purification via preparative HPLCprovided Example FY-5 (0.0057 g, 17%) as a yellow wax. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 8.47-8.76 (2 H, m), 7.93 (2 H, d, J=8.5 Hz), 7.68 (2 H,d, J=7.9 Hz), 7.18-7.62 (15 H, m), 6.34-6.68 (2 H, m), 5.12-5.34 (2 H,m), 4.04-4.29 (2 H, m), 3.42-3.92 (6 H, m), 3.36 (1 H, d, J=15.3 Hz),3.18-3.27 (1 H, m), 2.94-3.06 (2 H, m), 2.05 (2 H, br. s.), 1.85 (1 H,br. s.), 1.69 (1 H, br. s.); LC/MS (Cond. 1V): R_(t)=1.61 min; Anal.Calc. for [M+H]⁺ C₄₁H₄₂N₇O₇: 744.32; found: 744.51.

Example FY-6

Prepared according to the procedure described for Example FY-5. Thisafforded Example FY-6 (0.0057 g, 17% yield) as a yellow powder. ¹H NMR(500 MHz, DMSO-d₆) δ ppm 8.69 (1 H, d, J=7.3 Hz), 8.57 (1 H, d, J=7.6Hz), 7.88-7.99 (2 H, m), 7.64-7.74 (2 H, m), 7.19-7.64 (15 H, m),6.37-6.68 (2 H, m), 5.17-5.34 (2 H, m), 4.17 (4 H, br. s.), 3.69 (2 H,d, J=4.9 Hz), 3.43-3.59 (2 H, m), 3.29-3.43 (2 H, m), 3.14-3.26 (2 H,m), 2.10 (1 H, d, J=2.4 Hz), 1.97 (1 H, br. s.), 1.78 (2 H, br. s.);LC/MS (Cond. 1V): R_(t)=1.647 min; Anal. Calc. for [M+H]⁺ C₄₁H₄₂N₇O₇:744.32; found: 744.50.

Example FY-7

Prepared according to the procedure described for Example FY-5. Thisafforded Example FY-7 (0.0090 g, 26% yield) as a yellow powder. ¹H NMR(500 MHz, DMSO-d₆) δ ppm 8.27-8.75 (2 H, m), 7.87-7.97 (2 H, m),7.63-7.72 (2 H, m), 7.22-7.63 (13 H, m), 6.96-7.11 (2 H, m), 6.43-6.57(1 H, m), 6.11-6.25 (1 H, m), 4.03 (4 H, ddd, J=12.4, 6.1, 6.0 Hz),3.77-3.86 (1 H, m), 3.65-3.75 (1 H, m), 3.55-3.63 (1 H, m), 3.47-3.55 (1H, m), 3.36-3.46 (1 H, m), 3.28 (1 H, d, J=11.6 Hz), 2.91 (1 H, d, J=4.9Hz), 2.63-2.74 (1 H, m), 1.92-2.04 (1 H, m), 1.63-1.83 (1 H, m),1.46-1.63 (8 H, m); LC/MS (Cond. 1V): R_(t)=1.733 min; Anal. Calc. for[M+H]⁺ C₄₃H₄₆N₇O₇: 772.35; found: 772.56.

Example FY-8

Prepared according to the procedure described for Example FY-5. Thisafforded Example FY-8 (0.0146 g, 40% yield) as a yellow powder. ¹H NMR(500 MHz, DMSO-d₆) δ ppm 8.91-9.17 (1 H, m), 8.61-8.83 (1 H, m), 7.94 (2H, d, J=8.9 Hz), 7.69 (2 H, d, J=8.5 Hz), 7.34-7.63 (15 H, m), 6.85-7.07(1 H, m), 6.41-6.66 (1 H, m), 5.32-5.57 (2 H, m), 4.22-4.36 (1 H, m),3.97-4.15 (2 H, m), 3.76-3.89 (1 H, m), 3.45-3.64 (3 H, m), 3.33-3.44 (1H, m), 3.05 (1 H, d, J=7.9 Hz), 2.95 (6 H, br. s.), 2.72-2.83 (1 H, m),2.43 (6 H, br. s.), 2.00-2.19 (2 H, m), 1.93 (1 H, br. s.), 1.70 (1 H,td, J=7.8, 3.7 Hz); LC/MS (Cond. 1): R_(t)=1.318 min; Anal. Calc. for[M+H]⁺ C₄₅H₅₂N₉O₅: 798.41; found: 798.66.

Example FY-9

Example FY-9a

Prepared according to the procedure described for Example FY-5c, usingpyrazolidine as a starting material. This afforded Example FY-9a (0.0453g, 26% yield) as a yellow powder. ¹H NMR (500 MHz, DMSO-d₆) δ ppm8.96-9.25 (2 H, m), 7.93 (2 H, d, J=8.9 Hz), 7.52-7.87 (9 H, m), 3.41 (4H, d, J=2.4 Hz), 2.84 (4 H, d, J=4.9 Hz), 1.91-2.13 (4 H, m); LC/MS(Cond. 1V): R_(t)=1.278 min; Anal. Calc. for [M+H]⁺ C₂₃H₂₆N₇O₃: 448.21;found: 448.42.

Example FY-9b

To a stirred solution of (R)-2-(dimethylamino)-2-phenylacetic acid(0.0944 g, 0.438 mmol) (Cap 1) in CH₂Cl₂ (2 mL) was slowly added 2Moxalyl chloride (284 uL, 0.569 mmol) and one drop of DMF at 0° C. Aftertwo hours, the reaction was concentrated in vacuo to give Example FY-9b(0.241 g, 100%) as a light brown wax which was used in the next stepwithout further characterization or purification.

Example FY-9

Prepared according to the procedure described for Example OL-34. Thisafforded Example FY-9 (0.002, 12% yield) as a yellow wax. ¹H NMR (500MHz, DMSO-d₆) δ ppm 9.67-9.90 (2 H, m), 8.06 (2 H, d, J=8.9 Hz), 7.89 (2H, d, J=8.9 Hz), 7.10-7.87 (15 H, m), 5.46-5.76 (2 H, m), 3.71-4.24 (4H, m), 3.12-3.37 (2 H, m), 3.03 (6 H, d, J=3.1 Hz), 2.44 (6 H, d, J=3.7Hz), 1.83-2.23 (2 H, m), 1.71 (4 H, br. s.); LC/MS (Cond. 1V):R_(t)=1.198 min; Anal. Calc. for [M+H]⁺ C₄₃H₄₇N₉O₅: 770.38; found:770.62.

Examples RK-1 to RK-42

Examples RK-1 to RK-42 were prepared from Example CB-1c and 2.0 eq. ofthe appropriate, commercially-available or synthesized carboxylic acidsaccording to the procedure described for the preparation of ExampleCB-1. Purification of the final targets was accomplished using aShimadzu reverse phase preparative HPLC instrument (solvent systems:H₂O/MeOH/TFA or H₂O/ACN/TFA) and the final products were isolated as TFAsalts. The coupling partner (RCOOH) was obtained from commercial sourcesunless otherwise noted.

Example RCOOH Analysis RK-1

LCMS: Anal. Calcd. For [M + H]⁺: C₄₀H₃₉N₆O₇ 715.29; Found: 715.28. R_(t)= 1.41 min Cond. RK1 RK-2

LCMS: Anal. Calcd. For [M + H]⁺: C₄₀H₃₅N₆O₉ 743.25; Found: 743.41. R_(t)= 1.61 min Cond. RK1 RK-3

LCMS: Anal. Calcd. For [M + H]⁺: C₄₀H₃₉N₆O₅ 683.30; Found: 683.28. R_(t)= 1.43 min Cond. RK1 RK-4

LCMS: Anal. Calcd. For [M + H]⁺: C₄₂H₄₃N₆O₇ 743.32; Found: 743.31. R_(t)= 1.81 min Cond. RK1 RK-5

LCMS: Anal. Calcd. For [M + H]⁺: C₄₂H₄₃N₆O₇ 743.32; Found: 743.32. R_(t)= 1.85 min Cond. RK1 RK-6

LCMS: Anal. Calcd. For [M + H]⁺: C₄₀H₃₉N₆O₇ 715.29; Found: 715.26. R_(t)= 1.26 min Cond. RK1 RK-7

LCMS: Anal. Calcd. For [M + H]⁺: C₄₀H₃₉N₆O₇ 715.29; Found: 715.28. R_(t)= 1.31 min Cond. RK1 RK-8

LCMS: Anal. Calcd. For [M + H]⁺: C₄₂H₄₃N₆O₇ 743.32; Found: 743.31. R_(t)= 1.37 min Cond. RK1 RK-9

LCMS: Anal. Calcd. For [M + H]⁺: C₄₂H₄₃N₆O₅ 711.33; Found: 711.32. R_(t)= 1.54 min Cond. RK1 RK-10

LCMS: Anal. Calcd. For [M + H]⁺: C₄₄H₃₆N₈O₅ 757.29; Found: 757.33. R_(t)= 1.28 min Cond. RK1 RK-11

LCMS: Anal. Calcd. For [M + H]⁺: C₄₂H₄₃N₆O₇ 743.32; Found: 743.33. R_(t)= 1.33 min Cond. RK1 RK-12

LCMS: Anal. Calcd. For [M + H]⁺: C₃₆H₃₁Cl₂N₈O₅ 725.18; Found: 727.17.R_(t) = 1.25 min Cond. RK1 RK-13

LCMS: Anal. Calcd. For [M + H]⁺: C₃₆H₃₁N₈O₅ 635.23; Found: 635.22. R_(t)= 1.14 min Cond. RK1 RK-14

LCMS: Anal. Calcd. For [M + H]⁺: C₃₄H₃₉N₆O₇ 643.29; Found: 643.27. R_(t)= 1.07 min Cond. RK1 RK-15

LCMS: Anal. Calcd. For [M + H]⁺: C₃₄H₃₉N₆O₇ 643.29; Found: 643.27. R_(t)= 1.03 min Cond. RK1 RK-16

LCMS: Anal. Calcd. For [M + H]⁺: C₄₀H₃₉N₆O₇ 715.29; Found: 715.27. R_(t)= 1.21 min Cond. RK1 RK-17

LCMS: Anal. Calcd. For [M + H]⁺: C₄₀H₃₉N₆O₇ 715.29; Found: 715.28. R_(t)= 1.21 min Cond. RK1 RK-18

LCMS: Anal. Calcd. For [M + H]⁺: C₄₄H₃₅Cl₂N₈O₅ 825.21; Found: 825.42.R_(t) = 1.83 min Cond. RK1 RK-19

LCMS: Anal. Calcd. For [M + H]⁺: C₃₈H₃₉N₆O₇ 691.29; Found: 691.27. R_(t)= 1.22 min Cond. RK1 RK-20

LCMS: Anal. Calcd. For [M + H]⁺: C₃₂H₂₇Cl₂N₈O₅ 673.15; Found: 673.14.R_(t) = 1.42 min Cond. RK1 RK-21

LCMS: Anal. Calcd. For [M + H]⁺: C₃₀H₂₇N₆O₇ 583.19; Found: 583.17. R_(t)= 1.13 min Cond. RK1 RK-22

LCMS: Anal. Calcd. For [M + H]⁺: C₄₂H₃₇N₈O₇ 765.28; Found: 765.29. R_(t)= 1.78 min Cond. RK1 RK-23

LCMS: Anal. Calcd. For [M + H]⁺: C₃₆H₃₅N₆O₅ 631.27; Found: 631.28. R_(t)= 1.24 min Cond. RK1 RK-24

LCMS: Anal. Calcd. For [M + H]⁺: C₃₆H₃₅N₆O₇ 663.26; Found: 663.24. R_(t)= 1.17 min Cond. RK1 RK-25

LCMS: Anal. Calcd. For [M + H]⁺: C₃₆H₃₁F₂N₈O₅ 693.24; Found: 693.22.R_(t) = 1.22 min Cond. RK1 RK-26

LCMS: Anal. Calcd. For [M + H]⁺: C₄₈H₄₅N₈O₇ 845.34; Found: 845.31. R_(t)= 1.36 min Cond. RK1 RK-27

LCMS: Anal. Calcd. For [M + H]⁺: C₃₆H₃₁Cl₂N₈O₅ 725.18; Found: 725.17.R_(t) = 1.23 min Cond. RK1 RK-28

LCMS: Anal. Calcd. For [M + H]⁺: C₄₂H₄₃N₆O₇ 743.32; Found: 743.32. R_(t)= 1.29 min Cond. RK1 RK-29

LCMS: Anal. Calcd. For [M + H]⁺: C₃₂H₂₇F₂N₈O₅ 641.21; Found: 641.19.R_(t) = 1.31 min Cond. RK1 RK-30

LCMS: Anal. Calcd. For [M + H]⁺: C₃₈H₃₉N₆O₇ 691.29; Found: 691.27. R_(t)= 1.27 min Cond. RK1 RK-31

LCMS: Anal. Calcd. For [M + H]⁺: C₃₈H₃₉N₆O₇ 691.29; Found: 691.29. R_(t)= 1.24 min Cond. RK1 RK-32

LCMS: Anal. Calcd. For [M + H]⁺: C₄₆H₃₉Cl₂N₈O₇ 885.23; Found: 885.46.R_(t) = 1.96 min Cond. RK1 RK-33

LCMS: Anal. Calcd. For [M + H]⁺: C₄₂H₃₅Cl₂N₈O₇ 833.20; Found: 833.22.R_(t) = 1.97 min Cond. RK1 RK-34

LCMS: Anal. Calcd. For [M + H]⁺: C₃₀H₃₅N₆O₇ 591.26; Found: 591.24. R_(t)= 1.05 min Cond. RK1 RK-35

LCMS: Anal. Calcd. For [M + H]⁺: C₃₀H₃₅N₆O₇ 591.26; Found: 591.25. R_(t)= 1.10 min Cond. RK1 RK-36

LCMS: Anal. Calcd. For [M + H]⁺: C₄₀H₃₁Cl₂N₈O₅ 773.18; Found: 773.13.R_(t) = 1.72 min Cond. RK1 RK-37

LCMS: Anal. Calcd. For [M + H]⁺: C₃₂H₂₇Cl₂N₈O₅ 673.15; Found: 673.16.R_(t) = 1.43 min Cond. RK1 RK-38

LCMS: Anal. Calcd. For [M + H]⁺: C₄₀H₄₅N₈O₅ 717.35; Found: 717.30. R_(t)= 1.07 min Cond. RK1 RK-39

LCMS: Anal. Calcd. For [M + H]⁺: C₄₄H₄₉N₈O₅ 769.38; Found: 769.33. R_(t)= 1.01 min Cond. RK1 RK-40

LCMS: Anal. Calcd. For [M + H]⁺: C₃₈H₃₅Cl₂N₈O₇ 785.20; Found: 785.19.R_(t) = 1.39 min Cond. RK1 RK-41

LCMS: Anal. Calcd. For [M + H]⁺: C₃₄H₃₁Cl₂N₈O₇ 733.18; Found: 733.19.R_(t) = 1.43 min Cond. RK1 RK-42

LCMS: Anal. Calcd. For [M + H]⁺: C₄₄H₄₁N₈O₅ 761.32; Found: 761.36. R_(t)= 1.46 min Cond. RK1

Examples JR-1 to JR-23

Examples JR-1 to JR-23 were prepared from Example D-4-d and 2.0 eq. ofthe appropriate, commercially-available or synthesized carboxylic acidaccording to the procedure described for Example D-57. Purification ofthe final targets was accomplished using a Shimadzu reverse phasepreparative HPLC instrument (solvent systems: H₂O/MeOH/TFA orH₂O/ACN/TFA) and the final products were isolated as TFA salts. Thecoupling partner (ROH) was obtained from commercial sources unlessotherwise noted.

R_(t) (LC- Cond.); Coupling %; MS Example Protocol R data JR-1 HATU,DIPEA, DMF

LRMS: Anal. Calcd. For [M + H]⁺: C₄₇H₄₂N₇O₇ 816.31; Found: 816.04. R_(t)= 1.50 min Cond. -J2 JR-2 HATU, DIPEA, DMF

LRMS: Anal. Calcd. For [M + H]⁺: C₃₁H₃₀F₆N₅O₇ 698.21; Found: 698.55.R_(t) = 1.74 min Cond. -J2 JR-3 HATU, DIPEA, DMF

LRMS: Anal. Calcd. For [M + H]⁺: C₃₇H₄₀N₉O₇ 722.31; Found: 722.66. R_(t)= 1.19 min Cond. -J2 JR-4 HATU, DIPEA, DMF

LRMS: Anal. Calcd. For [M + H]⁺: C₄₁H₄₂N₇O₇ 744.31; Found: 744.73. JR-5HATU, DIPEA, DMF

LRMS: Anal. Calcd. For [M + H]⁺: C₄₇H₄₆N₇O₇ 820.35; Found: 820.80. JR-6HATU, DIPEA, DMF

LRMS: Anal. Calcd. For [M + H]⁺: C₃₇H₃₆N₅O₇S₂ 726.21; Found: 726.61.JR-7 HATU, DIPEA, DMF

LRMS: Anal. Calcd. For [M + H]⁺: C₃₉H₃₈N₇O₇ 716.28; Found: 716.31. R_(t)= 1.21 min Cond. -J2 JR-8 HATU, DIPEA, DMF

LRMS: Anal Calcd. For [M + H]⁺: C₄₇H₅₂Br₂N₇O₅ 952.24; Found: 952.14.R_(t) = 1.69 min Cond. -J1 JR-9 HATU, DIPEA, DMF

LRMS: Anal. Calcd. For [M + H]⁺: C₄₃H₄₀N₉O₇ 794.31; Found: 794.35. R_(t)= 1.83 min Cond. -J1 JR-10 HATU, DIPEA, DMF

LRMS: Anal. Calcd. For [M + H]⁺: C₄₉H₅₂N₉O₇ 878.40; Found: 878.40. R_(t)= 2.09 min Cond. -J1 JR-11 HATU, DIPEA, DMF

LRMS: Anal. Calcd. For [M + H]⁺: C₅₅H₄₈N₉O₇ 946.37; Found: 946.43. R_(t)= 2.14 min Cond. -J1 JR-12 HATU, DIPEA, DMF

LRMS: Anal. Calcd. For [M + H]⁺: C₃₉H₄₈N₁₃O₅ 778.39; Found: 778.41.R_(t) = 1.36 min Cond. -J1 JR-13 HATU, DIPEA, DMF

LRMS: Anal. Calcd. For [M + H]⁺: C₄₇H₅₄N₇O₇ 828.41; Found: 828.41. R_(t)= 1.67 min Cond. -J1 JR-14 HATU, DIPEA, DMF

LRMS: Anal. Calcd. For [M + H]⁺: C₄₇H₅₄N₇O₇ 828.41; Found: 828.42. R_(t)= 1.58 min Cond. -J1 JR-15 HATU, DIPEA, DMF

LRMS: Anal. Calcd. For [M + H]⁺: C₄₃H₅₀N₇O₇S₂ 840.32; Found: 840.43.R_(t) = 1.61 min Cond. -J1 JR-16 HATU, DIPEA, DMF

LRMS: Anal. Calcd. For [M + H]⁺: C₄₃H₅₀N₇O₇S₂ 840.32; Found: 840.42.R_(t) = 1.62 min Cond. -J1 JR-17 HATU, DIPEA, DMF

LRMS: Anal. Calcd. For [M + H]⁺: C₃₉H₄₂N₇O₇S₂ 784.26; Found: 784.13.R_(t) = 1.89 min Cond. -J1 JR-18 HATU, DIPEA, DMF

LRMS: Anal. Calcd. For [M + H]⁺: C₄₉H₅₄N₇O₉ 884.40; Found: 884.25. R_(t)= 2.04 min Cond. -J1 JR-19 HATU, DIPEA, DMF

LRMS: Anal. Calcd. For [M + H]⁺: C₅₃H₅₈N₇O₉ 936.43; Found: 936.23. R_(t)= 2.22 min Cond. -J1 JR-20 HATU, DIPEA, DMF

LRMS: Anal. Calcd. For [M + H]⁺: C₄₇H₄₆N₇O₉ 852.34; Found: 852.36. JR-21HATU, DIPEA, DMF

LRMS: Anal. Calcd. For [M + H]⁺: C₄₇H₄₆N₇O₉ 852.34; Found: 852.26. R_(t)= 1.96 min Cond. -J1 JR-22 HATU, DIPEA, DMF

LRMS: Anal. Calcd. For [M + H]⁺: C₄₇H₄₂N₇O₁₁, 880.29; Found: 880.21.

Examples XY-1 to XY-43

Examples XY-1 to XY-44 were prepared from Example D-4-d and 2.0 eq. ofthe appropriate, commercially-available or synthesized carboxylic acidaccording to the procedure described for Example D-57. Purification ofthe final targets was accomplished using a Shimadzu reverse phasepreparative HPLC instrument (solvent systems: H₂O/MeOH/TFA orH₂O/ACN/TFA). The coupling partner (ROH) obtained from commercialsources unless otherwise noted.

Example R XY-1

XY-2

XY-3

XY-4

XY-5

XY-6

XY-7

XY-8

XY-9

XY-10

XY-11

XY-12

XY-13

XY-14

XY-15

XY-16

XY-17

XY-18

XY-19

XY-20

XY-21

XY-22

XY-23

XY-24

XY-25

XY-25

XY-27

XY-28

XY-29

XY-30

XY-31

XY-31

XY-33

XY-34

XY-35

XY-36

XY-37

XY-38

XY-39

XY-40

XY-41

XY-42

XY-43

Examples XY-44 to XY-58

Examples XY-44 to XY-58 were prepared according to the method describedto prepare Example D-4 using L-trans-hydroxyproline and 2.0 eq. of theappropriate, commercially-available or synthesized carboxylic acidaccording to the procedure described for Example D-57. Purification ofthe final targets was accomplished using a Shimadzu reverse phasepreparative HPLC instrument (solvent systems: H₂O/MeOH/TFA orH₂O/ACN/TFA). The coupling partner (ROH) obtained from commercialsources unless otherwise noted.

Example R XY-44

XY-45

XY-46

XY-47

XY-48

XY-49

XY-50

XY-51

XY-52

XY-53

XY-54

XY-55

XY-56

XY-57

XY-58

Examples XY-59 to XY-77

Examples XY-59 to XY-77 were prepared according to the method describedto prepare Example D-4 using L-trans-t-butoxyproline and 2.0 eq. of theappropriate, commercially-available or synthesized carboxylic acidaccording to the procedure described for Example D-57. Purification ofthe final targets was accomplished using a Shimadzu reverse phasepreparative HPLC instrument (solvent systems: H₂O/MeOH/TFA orH₂O/ACN/TFA). The coupling partner (ROH) obtained from commercialsources unless otherwise noted.

Example R XY-59

XY-60 H XY-61

XY-62

XY-63

XY-64

XY-65

XY-66

XY-67

XY-68

XY-69

XY-70

XY-71

XY-72

XY-73

XY-74

XY-75

XY-76

XY-77

BIOLOGICAL ACTIVITY

An HCV Replicon assay was utilized in the present disclosure, and wasprepared, conducted and validated as described in commonly ownedPCT/US2006/022197 and in O'Boyle et al., Antimicrob. Agents Chemother,49(4):1346-1353 (April 2005). Assay methods incorporating luciferasereporters have also been used as described (Apath.com).

HCV-neo replicon cells and replicon cells containing resistancesubstitutions in the NS5A region were used to test the currentlydescribed family of compounds.

The compounds were determined to have differing degrees of reducedinhibitory activity on cells containing mutations vs. the correspondinginhibitory potency against wild-type cells. Thus, the compounds of thepresent disclosure can be effective in inhibiting the function of theHCV NS5A protein and are understood to be as effective in combinationsas previously described in application PCT/US2006/022197 and commonlyowned WO 04/014852. It should be understood that the compounds of thepresent disclosure can inhibit multiple genotypes of HCV. Table 2 showsthe EC₅₀ (Effective 50% inhibitory concentration) values ofrepresentative compounds of the present disclosure against the HCV 1bgenotype. In one embodiment, compounds of the present disclosure areinhibitory versus 1a, 1b, 2a, 2b, 3a, 4a, and 5a genotypes. EC₅₀ rangesagainst HCV 1b are as follows: A (1-10 μM); B (100-999 nM); C (4.57-99nM); D (<4.57 nM).

TABLE 2 Example 1b (μM) Range Name OL-1 A 4,5-bis[4-[[(2S)-1-oxo-2-[[(phenylmethoxy)carbonyl]amino]propyl]amino]phenyl]- 2-oxazoleaceticacid OL-1d A 4,5-bis[4-[[(2S)-1-oxo-2-[[(phenylmethoxy)carbonyl]amino]propyl]amino]phenyl]- 2-oxazoleaceticacid, ethyl ester OL-2 A4,5-bis[4-[[[(2S)-1-[(phenylmethoxy)carbonyl]-2-pyrrolidinyl]carbonyl]amino]phenyl]-2-oxazoleacetic acid, ethyl esterOL-3 A 4,5-bis[4-[[[(2S)-1-[(phenylmethoxy)carbonyl]-2-pyrrolidinyl]carbonyl]amino]phenyl]-2-oxazoleacetic acid OL-4 0.22 B[(2-methyl-4,5-oxazolediyl)bis[4,1-phenyleneimino[(1S)-1-methyl-2-oxo-2,1- ethanediyl]]]bis-carbamic acid,bis(phenylmethyl) ester OL-5 B(2S,2′S)-2,2′-[(2-methyl-4,5-oxazolediyl)bis(4,1-phenyleneiminocarbonyl)]bis-1-pyrrolidinecarboxylic acid,bis(phenylmethyl) ester OL-6 A(2S,2′S)-N,N′-[[2-[(dimethylamino)methyl]-4,5-oxazolediyl]di-4,1-phenylene]bis[1-(phenylacetyl)-2-pyrrolidinecarboxamide MS-1 B(2S)-1-acetyl-N-(4-(2-(4-((((2S)-1-(phenylacetyl)-2-pyrrolidinyl)carbonyl)amino)phenyl)-1,3-oxazol-5-yl)phenyl)-2-pyrrolidinecarboxamide MS-2 B benzyl(2S,4R)-2-((4-(5-(4-((((2S)-1-acetyl-2-pyrrolidinyl)carbonyl)amino)phenyl)-1,3-oxazol-2-yl)phenyl)carbamoyl)-4-tert-butoxy-1- pyrrolidinecarboxylate MS-3 Bbenzyl (2S,4R)-2-((4-(5-(4-((((2S)-1-acetyl-2-pyrrolidinyl)carbonyl)amino)phenyl)-1,3-oxazol-2-yl)phenyl)carbamoyl)-4-hydroxy-1- pyrrolidinecarboxylate MS-4 0.90070 Bbenzyl 3-((4-(5-(4-((1-acetyl-L-prolyl)amino)phenyl)-1,3-oxazol-2-yl)phenyl)carbamoyl)-1- pyrrolidinecarboxylate MS-5 B(2S)-1-acetyl-N-[4-[2-[4-[[[5-oxo-1-[2-(2-thienyl)ethyl]-3-pyrrolidinyl]carbonyl]amino]phenyl]-5-oxazolyl]phenyl]-2-pyrrolidinecarboxamide MS-6 0.1875 B(2S)-1-acetyl-N-(4-(5-(4-((((2S)-1-(phenylacetyl)-2-pyrrolidinyl)carbonyl)amino)phenyl)-1,3-oxazol-2-yl)phenyl)-2-pyrrolidinecarboxamide MS-7 A(2S)-N-[4-[5-[4-[[[(2S)-1-acetyl-2-pyrrolidinyl]carbonyl]amino]phenyl]-2-oxazolyl]phenyl]-2,5-dihydro-1-(2-thienylcarbonyl)-1H-pyrrole-2-carboxamide D-1 A (2S)-N-[4-[5-[4-[[[(2S)-1-acetyl-2-pyrrolidinyl]carbonyl]amino]phenyl]-2-oxazolyl]phenyl]-2,5-dihydro-1-(2-thienylacetyl)-1H-pyrrole-2-carboxamide D-2 B (2S)-N-[4-[5-[4-[[[(2S)-1-acetyl-2-pyrrolidinyl]carbonyl]amino]phenyl]-2-oxazolyl]phenyl]-1-(2-ethylbenzoyl)-2,5-dihydro-1H-pyrrole-2-carboxamide D-3 A (2S)-N-[4-[5-[4-[[[(2S)-1-acetyl-2-pyrrolidinyl]carbonyl]amino]phenyl]-2-oxazolyl]phenyl]-2,5-dihydro-1-(5-isoxazolylcarbonyl)-1H-pyrrole-2-carboxamide D-4 D(2S,2′S)-N,N′-(2,5-oxazolediyldi-4,1-phenylene)bis[1-[(dimethylamino)(2-fluorophenyl)acetyl]-2- pyrrolidinecarboxamide] D-5 D(2S,2′S)-N,N′-(2,5-oxazolediyldi-4,1-phenylene)bis[1-[(2,4-difluorophenyl)(dimethylamino)acetyl]-2- pyrrolidinecarboxamide]D-6 D (2S,2′S)-N,N′-(2,5-oxazolediyldi-4,1-phenylene)bis[1-[(2,4-difluorophenyl)(dimethylamino)acetyl]-2- pyrrolidinecarboxamide]D-7 C ((2S,2′S)-N,N′-(2,5-oxazolediyldi-4,1-phenylene)bis[1-[(2,4-difluorophenyl)(dimethylamino)acetyl]-2- pyrrolidinecarboxamide]D-8 C (2S,2′S)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(1-((4-methyl-1-piperazinyl)(phenyl)acetyl)-2-pyrrolidinecarboxamide) D-9 3.33 A(2S,2′S)-N,N′-(4,4′-(oxazole-2,5-diyl)bis(4,1-phenylene))bis(1-(2-(5,6-difluoro-3-isopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1- yl)acetyl)pyrrolidine-2-carboxamide)D-10 B (2S,2′S)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(1-(hydroxy(1,3-thiazol-2-yl)acetyl)-2-pyrrolidinecarboxamide) D-11 2.09 A(2S,2′S)-N,N′-(4,4′-(oxazole-2,5-diyl)bis(4,1-phenylene))bis(1-(2-hydroxy-2-(1-methyl-1H-imidazol-2-yl)acetyl)pyrrolidine-2-carboxamide) D-12 2.36 A diethyl4,4′-(2,2′-(2S,2′S)-2,2′-(4,4′-(oxazole-2,5- diyl)bis(4,1-phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2,1-diyl)bis(1-hydroxy-2-oxoethane-2,1-diyl))bis(1H-pyrrole-2-carboxylate) D-13(2S,2′S)-N,N′-(4,4′-(oxazole-2,5-diyl)bis(4,1-phenylene))bis(1-(2-hydroxy-2-(imidazo[1,2-a]pyridin-3-yl)acetyl)pyrrolidine-2-carboxamide) D-14 B(2S,2′S)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(1-(hydroxy(2-pyridinyl)acetyl)-2- pyrrolidinecarboxamide)D-15 6.83 A (2S,2′S)-N,N′-(4,4′-(oxazole-2,5-diyl)bis(4,1-phenylene))bis(1-(2-hydroxy-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)acetyl)pyrrolidine-2-carboxamide) D-16(2S,2′S)-N,N′-(4,4′-(oxazole-2,5-diyl)bis(4,1-phenylene))bis(1-(2-hydroxy-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)acetyl)pyrrolidine-2-carboxamide) D-17 6.82 A(2S,2′S)-N,N′-(4,4′-(oxazole-2,5-diyl)bis(4,1-phenylene))bis(1-(2-hydroxy-2-(1H-pyrrolo[2,3-c]pyridin-3-yl)acetyl)pyrrolidine-2-carboxamide) D-18 5.96 A(R,S,2S,2′S)-N,N′-(4,4′-(oxazole-2,5-diyl)bis(4,1-phenylene))bis(1-((2R,3S)-2-benzamido-3-hydroxybutanoyl)pyrrolidine-2-carboxamide) D-19 B(2S,2′S)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(1-(2-(4-chlorophenoxy)-3-(dimethylamino)propanoyl)-2-pyrrolidinecarboxamide) D-20 B(2′S)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(1-(cyclopropylacetyl)-2-pyrrolidinecarboxamide) D-21 A(2S,2′S)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(1-((1-benzyl-2-piperidinyl)carbonyl)-2-pyrrolidinecarboxamide) D-22 B(2S,2′S)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(1-((1-(cyclohexylmethyl)-2-piperidinyl)carbonyl)-2-pyrrolidinecarboxamide) D-23 A(2S,2′S)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(1-((1-benzyl-2-methyl-5-oxo-2-pyrrolidinyl)carbonyl)-2-pyrrolidinecarboxamide) D-24 5.14 A(2S,2′S)-N,N′-(4,4′-(oxazole-2,5-diyl)bis(4,1-phenylene))bis(1-(2-methyl-5-oxopyrrolidine-2-carbonyl)pyrrolidine-2-carboxamide) D-25 5.33 A(2S,2′S)-N,N′-(4,4′-(oxazole-2,5-diyl)bis(4,1-phenylene))bis(1-(2,4,4-trimethyl-5-oxopyrrolidine-2-carbonyl)pyrrolidine-2-carboxamide) D-26 3.33 A(S,S,S,2S,2′S)-N,N′-(4,4′-(oxazole-2,5-diyl)bis(4,1-phenylene))bis(1-((1S,3S,5S)-2-(2,4-dichlorobenzoyl)-2-azabicyclo[3.1.0]hexane-3-carbonyl)pyrrolidine-2- carboxamide) D-27 Adi-tert-butyl (2S,2′S)-2,2′-(1,3-oxazole-2,5-diylbis(4,1-phenylenecarbamoyl(2S)-2,1-pyrrolidinediylcarbonyl))di(1-pyrrolidinecarboxylate) D-28 Adi-tert-butyl (2R,2′R)-2,2′-(1,3-oxazole-2,5-diylbis(4,1-phenylenecarbamoyl(2S)-2,1-pyrrolidinediylcarbonyl))di(1-pyrrolidinecarboxylate) D-29 Adi-tert-butyl 2,2′-(1,3-oxazole-2,5-diylbis(4,1-phenylenecarbamoyl(2S)-2,1- pyrrolidinediylcarbonyl))bis(2-methyl-1-pyrrolidinecarboxylate) D-30 A di-tert-butyl2,2′-(1,3-oxazole-2,5-diylbis(4,1- phenylenecarbamoyl(2S)-2,1-pyrrolidinediylcarbonyl))bis(2-methyl-1- pyrrolidinecarboxylate) D-31 Adi-tert-butyl (1S,3S,5S,1′S,3′S,5′S)-3,3′-(1,3-oxazole-2,5-diylbis(4,1-phenylenecarbamoyl(2S)-2,1-pyrrolidinediylcarbonyl))bis(2- azabicyclo[3.1.0]hexane-2-carboxylate)D-32 A di-tert-butyl 2,2′-(1,3-oxazole-2,5-diylbis(4,1-phenylenecarbamoyl(2S)-2,1- pyrrolidinediylcarbonyl))bis(2-benzyl-1-pyrrolidinecarboxylate) D-33 A di-tert-butyl2,2′-(1,3-oxazole-2,5-diylbis(4,1- phenylenecarbamoyl(2S)-2,1-pyrrolidinediylcarbonyl))bis(2-benzyl-1- pyrrolidinecarboxylate) D-34 A(2S,2′S)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(1-((2S)-2-pyrrolidinylcarbonyl)-2- pyrrolidinecarboxamide)D-35 5.24 A (2S,2′S)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(1-((2R)-2-pyrrolidinylcarbonyl)-2- pyrrolidinecarboxamide)D-36 A (2S,2′S)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(1-((2-methyl-2-pyrrolidinyl)carbonyl)-2-pyrrolidinecarboxamide) D-37 A(2S,2′S)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(1-((2-benzyl-2-pyrrolidinyl)carbonyl)-2-pyrrolidinecarboxamide) D-38 0.11 B(2S,2′S)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(1-(((2S)-1-((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidinyl)carbonyl)-2- pyrrolidinecarboxamide) D-39 A(2S,2′S)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(1-(((2R)-1-((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidinyl)carbonyl)-2- pyrrolidinecarboxamide) D-40 B(2S,2′S)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(1-(((1S,3S,5S)-2-((2R)-2-(dimethylamino)-2-phenylacetyl)-2-azabicyclo[3.1.0]hex-3-yl)carbonyl)-2- pyrrolidinecarboxamide) D-41 B(2S,2′S)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(1-((1-((2R)-2-(dimethylamino)-2-phenylacetyl)-2-methyl-2-pyrrolidinyl)carbonyl)-2-pyrrolidinecarboxamide) OL-7 C(2S,2′S)-2,2′-[1H-imidazole-4,5-diylbis(4,1-phenyleneiminocarbonyl)]bis-1-pyrrolidinecarboxylic acid,bis(phenylmethyl) ester OL-8 C[1H-imidazole-4,5-diylbis[4,1-phenyleneimino[(1S)-1-methyl-2-oxo-2,1-ethanediyl]]]bis-carbamic acid, bis(phenylmethyl) esterOL-9 A (2S,2′S)-N,N′-(1H-imidazole-4,5-diyldi-4,1-phenylene)bis(2-((phenylacetyl)amino)propanamide) OL-10 C(2S,2′S)-N,N′-(1H-imidazole-4,5-diyldi-4,1-phenylene)bis(1-(phenylacetyl)-2- pyrrolidinecarboxamide) OL-11 B(2S,4S,2′S,4′S)-N,N′-(1H-imidazole-4,5-diyldi-4,1-phenylene)bis(4-hydroxy-1-(phenylacetyl)-2- pyrrolidinecarboxamide) D-42A (2S)-1-acetyl-N-(4-(2-methyl-4-(4-((((2S)-1-(phenylacetyl)-2-pyrrolidinyl)carbonyl)amino)phenyl)-1,3-thiazol-5-yl)phenyl)-2-pyrrolidinecarboxamide D-43 B(2S,2′S)-N,N′-((2-methyl-1,3-thiazole-4,5-diyl)di-4,1-phenylene)bis(1-acetyl-2-pyrrolidinecarboxamide) D-44 C(2S,2′S)-N,N′-((2-methyl-1,3-thiazole-4,5-diyl)di-4,1-phenylene)bis(1-(phenylacetyl)-2- pyrrolidinecarboxamide) D-45 B(2S)-1-acetyl-N-(4-(4-(4-((((2S)-1-(phenylacetyl)-2-pyrrolidinyl)carbonyl)amino)phenyl)-1,3-thiazol-2-yl)phenyl)-2-pyrrolidinecarboxamide D-46 A(2S)-1-acetyl-N-[4-[4-[4-[[[5-oxo-1-[2-(2-thienyl)ethyl]-3-pyrrolidinyl]carbonyl]amino]phenyl]-2-thiazolyl]phenyl]-2-pyrrolidinecarboxamide D-47 A(2S)-N-[4-[2-[4-[[[(2S)-1-acetyl-2-pyrrolidinyl]carbonyl]amino]phenyl]-4-thiazolyl]phenyl]-2,5-dihydro-1-(2-thienylcarbonyl)-1H-pyrrole-2-carboxamide D-48 B (2S)-N-[4-[2-[4-[[[(2S)-1-acetyl-2-pyrrolidinyl]carbonyl]amino]phenyl]-4-thiazolyl]phenyl]-2,5-dihydro-1-(2-thienylacetyl)-1H-pyrrole-2-carboxamide D-49 A (2S)-N-[4-[2-[4-[[[(2S)-1-acetyl-2-pyrrolidinyl]carbonyl]amino]phenyl]-4-thiazolyl]phenyl]-2,5-dihydro-1-(phenylacetyl)-1H- pyrrole-2-carboxamideD-50 B (2S)-N-[4-[2-[4-[[[(2S)-1-acetyl-2-pyrrolidinyl]carbonyl]amino]phenyl]-4-thiazolyl]phenyl]-2,5-dihydro-1-(5-isoxazolylcarbonyl)-1H-pyrrole-2-carboxamide D-51 3.43 A(2S)-N-[4-[2-[4-[[[(2S)-1-acetyl-2-pyrrolidinyl]carbonyl]amino]phenyl]-4-thiazolyl]phenyl]-2,5-dihydro-1-[[(2R)-tetrahydro-2-furanyl]carbonyl]-1H-pyrrole-2-carboxamide D-52 A(2S)-N-[4-[2-[4-[[[(2S)-1-acetyl-2-pyrrolidinyl]carbonyl]amino]phenyl]-4-thiazolyl]phenyl]-2,5-dihydro-1-[[(2S)-tetrahydro-2-furanyl]carbonyl]-1H-pyrrole-2-carboxamide D-53 1.13 A(2S)-N-[4-[2-[4-[[[(2S)-1-acetyl-2-pyrrolidinyl]carbonyl]amino]phenyl]-4-thiazolyl]phenyl]-1-benzoyl-2,5-dihydro-1H-pyrrole-2- carboxamide OL-12A [(1,5-dihydro-5-oxo-4H-1,2,4-triazole-3,4-diyl)bis[4,1-phenyleneimino[(1S)-1-methyl-2-oxo-2,1- ethanediyl]]]bis-carbamic acid,bis(phenylmethyl) ester OL-13 A(2S,2′S)-2,2′-[(1,5-dihydro-5-oxo-4H-1,2,4-triazole-3,4-diyl)bis(4,1-phenyleneiminocarbonyl)]bis-1- pyrrolidinecarboxylicacid, bis(phenylmethyl) ester, OL-14 A(2S,2′S)-2,2′-[4H-1,2,4-triazole-3,4-diylbis(4,1-phenyleneiminocarbonyl)]bis-1-pyrrolidinecarboxylic acid,bis(phenylmethyl) ester OL-15 A(2S,2′S)-N,N′-(4H-1,2,4-triazole-3,4-diyldi-4,1-phenylene)bis[1-(phenylacetyl)-2- pyrrolidinecarboxamide] OL-16 A[(1S)-1-methyl-2-oxo-2-[[4-[3-[4-[[(2S)-1-oxo-2-[[(phenylmethoxy)carbonyl]amino]propyl]amino]phenyl]-4H-1,2,4-triazol-4-yl]phenyl]amino]ethyl]-carbamic acid, phenylmethylester OL-17 A (2S,4R,2′S,4′R)-N,N′-(4H-1,2,4-triazole-3,4-diyldi-4,1-phenylene)bis[4-hydroxy-1-(phenylacetyl)-2- pyrrolidinecarboxamide] MS-80.09 C (2S,2′S)-2,2′-[1,3,4-oxadiazole-2,5-diylbis(4,1-phenyleneiminocarbonyl)]bis-1-pyrrolidinecarboxylic acid,bis(phenylmethyl) ester MS-9 0.15 B(2S,2′S)-N,N′-(4,4′-(1,3,4-oxadiazole-2,5-diyl)bis(4,1-phenylene))bis(1-(2-phenylacetyl)pyrrolidine-2- carboxamide) D-54 4.76 A(2S)-1-acetyl-N-[4-[5-[4-[[[(2S)-1-(phenylacetyl)-2-pyrrolidinyl]carbonyl]amino]phenyl]-1,3,4-oxadiazol-2-yl]phenyl]-2-pyrrolidinecarboxamide D-55 10 A(2S,2′S)-N,N′-(1,3,4-oxadiazole-2,5-diyldi-4,1-phenylene)bis[1-acetyl-2-pyrrolidinecarboxamide] D-56 0.15 B(2S,2′S)-N,N′-(1,3,4-oxadiazole-2,5-diyldi-4,1-phenylene)bis[1-(phenylacetyl)-2- pyrrolidinecarboxamide] D-57 1.95 A(2S,2′S)-N,N′-(1,3,4-oxadiazole-2,5-diyldi-4,1-phenylene)bis[1-(cyclopropylacetyl)-2- pyrrolidinecarboxamide] D-58 2.21A (2S,2′S)-N,N′-(1,3,4-oxadiazole-2,5-diyldi-4,1-phenylene)bis[1-(cyclopropylcarbonyl)-2- pyrrolidinecarboxamide] D-595.45 A (2S,2′S)-N,N′-(1,3,4-oxadiazole-2,5-diyldi-4,1-phenylene)bis[1-(cyclobutylcarbonyl)-2- pyrrolidinecarboxamide] D-600.65 B (S,2S,2′S)-N,N′-(4,4′-(1,3,4-oxadiazole-2,5-diyl)bis(4,1-phenylene))bis(1-((S)-tetrahydrofuran-2-carbonyl)pyrrolidine-2-carboxamide) D-61 0.327 B(2S,2′S)-N,N′-(4,4′-(1,3,4-oxadiazole-2,5-diyl)bis(4,1-phenylene))bis(1-(2-(thiophen-2-yl)acetyl)pyrrolidine- 2-carboxamide)D-62 3.467 A (2S)-1-acetyl-N-[4-[5-[4-[[[(2S)-1-(2-thienylacetyl)-2-pyrrolidinyl]carbonyl]amino]phenyl]-1,3,4-oxadiazol-2-yl]phenyl]-2-pyrrolidinecarboxamide D-63 1.938 A(2S,2′S)-N,N′-(1,3,4-oxadiazole-2,5-diyldi-4,1-phenylene)bis[1-(3-pyridinylacetyl)-2- pyrrolidinecarboxamide] D-64 6.57A (2S)-1-acetyl-N-[4-[5-[4-[[[(2S)-1-(3-pyridinylacetyl)-2-pyrrolidinyl]carbonyl]amino]phenyl]-1,3,4-oxadiazol-2-yl]phenyl]-2-pyrrolidinecarboxamide OL-18 0.092 C[(1S)-1-methyl-2-oxo-2-[[4-[4-[4-[[(2S)-1-oxo-2-[[(phenylmethoxy)carbonyl]amino]propyl]amino]phenyl]-1H-1,2,3-triazol-5-yl]phenyl]amino]ethyl]-carbamic acid, phenylmethylester OL-19 C (2S,2′S)-2,2′-[1H-1,2,3-triazole-4,5-diylbis(4,1-phenyleneiminocarbonyl)]bis-1-pyrrolidinecarboxylic acid,bis(phenylmethyl) ester OL-20 C(2S,2′S)-N,N′-(1H-1,2,3-triazole-4,5-diyldi-4,1-phenylene)bis[1-(phenylacetyl)-2- pyrrolidinecarboxamide] OL-21 B(2S,4R,2′S,4′R)-N,N′-(1H-1,2,3-triazole-4,5-diyldi-4,1-phenylene)bis(4-hydroxy-1-(phenylacetyl)-2- pyrrolidinecarboxamide)OL-22 C (2S,2′S)-N,N′-(2,5-thienediyldi-4,1-phenylene)bis(1-(phenylacetyl)-2-pyrrolidinecarboxamide) OL-23 C(2S,2′S)-2,2′-[2,5-thienediylbis(4,1-phenyleneiminocarbonyl)]bis-1-pyrrolidinecarboxylic acid,bis(phenylmethyl) ester OL-24 0.62 B(2S,2′S)-N,N′-(2,5-thienediyldi-4,1-phenylene)bis[1-acetyl-2-pyrrolidinecarboxamide] OL-25 C(2S,2′S)-N,N′-(2,5-thienediyldi-3,1-phenylene)bis[1-(phenylacetyl)-2-pyrrolidinecarboxamide] OL-26 C(2S,2′S)-2,2′-[1H-pyrazole-3,5-diylbis(4,1-phenyleneiminocarbonyl)]bis-1-pyrrolidinecarboxylic acid,bis(phenylmethyl) ester OL-27 0.01 C(2S,2′S)-N,N′-(1H-pyrazole-3,5-diyldi-4,1-phenylene)bis[1-(phenylacetyl)-2- pyrrolidinecarboxamide] OL-28 C(2S,4R,2′S,4′R)-N,N′-(1H-pyrazole-3,5-diyldi-4,1-phenylene)bis(4-hydroxy-1-(phenylacetyl)-2- pyrrolidinecarboxamide)OL-29 4.55 A (2S,2′S)-N,N′-(1H-pyrazole-3,5-diyldi-4,1-phenylene)bis(1-acetyl-2-pyrrolidinecarboxamide) OL-30 A(2S,2′S)-N,N′-(1H-pyrazole-3,5-diyldi-4,1-phenylene)bis(1-acetyl-2,5-dihydro-1H-pyrrole-2- carboxamide) OL-31 B(2S,2′S)-N,N′-(1H-pyrazole-3,5-diyldi-4,1-phenylene)bis(1-isobutyryl-2-pyrrolidinecarboxamide) OL-32 A(2S,2′S)-N,N′-(1H-pyrazole-3,5-diyldi-4,1-phenylene)bis(1-propionyl-2-pyrrolidinecarboxamide) OL-33 B(2S,2′S)-N,N′-(1H-pyrazole-3,5-diyldi-4,1-phenylene)bis(1-(cyclobutylcarbonyl)-2- pyrrolidinecarboxamide) OL-34 A(2S,2′S)-N,N′-(1H-pyrazole-3,5-diyldi-4,1-phenylene)bis(1-isonicotinoyl-2- pyrrolidinecarboxamide) OL-35 8.25 A(2S,2′S)-N,N′-(1H-pyrazole-3,5-diyldi-4,1-phenylene)bis(1-(cyclopropylcarbonyl)-2- pyrrolidinecarboxamide) OL-36 B(2S)-1-acetyl-N-(4-(3-(4-((((2S)-1-(phenylacetyl)-2-pyrrolidinyl)carbonyl)amino)phenyl)-1H-pyrazol-5-yl)phenyl)-2-pyrrolidinecarboxamide OL-37 A(2S,2′S)-N,N′-(1H-pyrazole-3,5-diyldi-4,1-phenylene)bis(1-(cyclopropylcarbonyl)-2,5-dihydro-1H-pyrrole-2-carboxamide) OL-38 10 A(2S,2′S)-N,N′-(1H-pyrazole-3,5-diyldi-4,1-phenylene)bis(1-(cyclobutylcarbonyl)-2,5-dihydro-1H-pyrrole-2-carboxamide) OL-39 A(2S,2′S)-N,N′-(1H-pyrazole-3,5-diyldi-4,1-phenylene)bis[1-(cyclopentylacetyl)-2,5-dihydro-1H-pyrrole-2-carboxamide] OL-40 C(2S,2′S)-N,N′-(1H-pyrazole-3,5-diyldi-4,1-phenylene)bis(1-((3-chloro-1-isoquinolinyl)carbonyl)-2-pyrrolidinecarboxamide) OL-41 C(2S,2′S)-N,N′-(1H-pyrazole-3,5-diyldi-4,1-phenylene)bis(1-((3-chloro-5-methoxy-1-isoquinolinyl)carbonyl)-2-pyrrolidinecarboxamide) OL-42 DN,N′-(1H-pyrazole-3,5-diyldi-4,1-phenylene)bis(1-((2R)-2-acetamido-2-phenylacetyl)-2- pyrrolidinecarboxamide) OL-43 C(S)-2-((S)-2-hydroxy-2-phenylacetamido)-N-(4-(5-(4-((R)-2-((S)-2-hydroxy-2-phenylacetamido)propanamido)phenyl)-1H-pyrazol-3- yl)phenyl)propanamideOL-44 D (S)-2-((R)-2-hydroxy-2-phenylacetamido)-N-(4-(5-(4-((R)-2-((R)-2-hydroxy-2-phenylacetamido)propanamido)phenyl)-1H-pyrazol-3- yl)phenyl)propanamideOL-45 D (2S,2′S)-N,N′-(1H-pyrazole-3,5-diylbis(4,1-phenyleneimino((2S)-1-oxo-1,2-propanediyl)))bis(2-hydroxy-2-phenylpropanamide) OL-46 C(2R,2′R)-N,N′-(1H-pyrazole-3,5-diylbis(4,1-phenyleneimino((2S)-1-oxo-1,2-propanediyl)))bis(2-hydroxy-2-phenylpropanamide) OL-47 C N,N′-(1H-pyrazole-3,5-diylbis(4,1-phenyleneimino((2S)-1-oxo-1,2-propanediyl)))bis(3- chloro-1-naphthamide)OL-48 0.28 B N,N′-(1H-pyrazole-3,5-diylbis(4,1-phenyleneimino((2S)-1-oxo-1,2-propanediyl)))bis(3-chloro-1-isoquinolinecarboxamide) OL-49 0.23 B dibenzyl(2S,4R,2′S,4′R)-2,2′-(1H-pyrazole-3,5-diylbis(4,1-phenylenecarbamoyl))bis(4-tert-butoxy-1-pyrrolidinecarboxylate) OL-50 B(2S,2′S)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(1-((6-fluoro-2-pyridinyl)carbonyl)-2-pyrrolidinecarboxamide) OL-51 C(2S)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(1-((2R)-2-(dimethylamino)-2-phenylacetyl)-2- pyrrolidinecarboxamide) OL-520.03 B (2S,2′S)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(1-((3-chloro-5-methoxy-1-isoquinolinyl)carbonyl)-2-pyrrolidinecarboxamide) OL-53 DN,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(1-((2R)-2-acetamido-2-phenylacetyl)-2- pyrrolidinecarboxamide) OL-54 C(2S,2′S)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(2-(((2S)-2-hydroxy-2- phenylacetyl)amino)propanamide)OL-55 D (2S,2′S)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(2-(((2R)-2-hydroxy-2- phenylacetyl)amino)propanamide)OL-56 D ((2S,2′S)-N,N′-(1,3-oxazole-2,5-diylbis(4,1-phenyleneimino((2S)-1-oxo-1,2-propanediyl)))bis(2-hydroxy-2-phenylpropanamide)) OL-57 C(2R,2′R)-N,N′-(1,3-oxazole-2,5-diylbis(4,1-phenyleneimino((2S)-1-oxo-1,2-propanediyl)))bis(2-hydroxy-2-phenylpropanamide)) OL-58 D(2S,4S,2′S,4′S)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(1-((2R)-2-hydroxy-2-phenylacetyl)-4-methoxy-2-pyrrolidinecarboxamide) OL-59 D(2S,4S,2′S,4′S)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(1-((2R)-2-(dimethylamino)-2-phenylacetyl)-4-methoxy-2-pyrrolidinecarboxamide) OL-60 C(2S,4S,2′S,4′S)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(1-(acetamido(phenyl)acetyl)-4-methoxy-2-pyrrolidinecarboxamide) OL-61 C (2S)-1-((3-chloro-5-methoxy-1-isoquinolinyl)carbonyl)-N-(4-(2-(4-((((2S)-1-((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidinyl)carbonyl)amino)phenyl)-1,3-oxazol-5-yl)phenyl)-2-pyrrolidinecarboxamide CB-1 <0.005 C(1S,3S,5S,1′S,3′S,5′S)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(2-((2R)-2-acetamido-2-phenylacetyl)-2-azabicyclo[3.1.0]hexane-3- carboxamide) CB-2 B(1S,3S,5S,1′S,3′S,5′S)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(2-(1-isoquinolinylcarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide) CB-3 0.38 B(1S,3S,5S,1′S,3′S,5′S)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(2-((3-chloro-1-isoquinolinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3- carboxamide) CB-4 B(1S,3S,5S,1′S,3′S,5′S)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(2-((3-chloro-5-methoxy-1-isoquinolinyl)carbonyl)-2-azabicyclo[3.1.0]hexane-3- carboxamide) CB-5 C(1S,3S,5S,1′S,3′S,5′S)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(2-((2S)-2-hydroxy-2-phenylacetyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide) CB-6 D(1S,3S,5S,1′S,3′S,5′S)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(2-((2R)-2-hydroxy-2-phenylacetyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide) CB-7 B(1S,3S,5S,1′S,3′S,5′S)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(2-((2R)-tetrahydro-2-furanylcarbonyl)-2-azabicyclo[3.1.0]hexane-3- carboxamide) CB-8 <0.005 D(1S,3S,5S,1′S,3′S,5′S)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(2-((2S)-2-hydroxy-2-phenylpropanoyl)-2-azabicyclo[3.1.0]hexane-3- carboxamide) CB-9 D(1S,3S,5S,1′S,3′S,5′S)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(2-((2R)-2-(dimethylamino)-2-phenylacetyl)-2-azabicyclo[3.1.0]hexane-3- carboxamide) CB-10 D(1S,3S,5S,1′S,3′S,5′S)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(2-((2R)-2-hydroxy-2-phenylpropanoyl)-2-azabicyclo[3.1.0]hexane-3- carboxamide) JG-1 Ddibenzyl (2S,2′S)-2,2′-(1,3-oxazole-2,5-diylbis(4,1-phenylenecarbamoyl))di(1-pyrrolidinecarboxylate) JG-2 0.002 D(2S,4R,2′S,4′R)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(4-hydroxy-1-(phenylacetyl)-2- pyrrolidinecarboxamide) JG-3D (2S,2′S)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(1-(phenylacetyl)-2- pyrrolidinecarboxamide) JG-4 Bdibenzyl (1,3-oxazole-2,5-diylbis(4,1-phenyleneimino((2S)-3-methyl-1-oxo-1,2- butanediyl)))biscarbamate JG-510 A dibenzyl (1,3-oxazole-2,5-diylbis(4,1-phenyleneimino((2R)-3-methyl-1-oxo-1,2- butanediyl)))biscarbamate JG-6 B(2S,2′S)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(1-(phenylacetyl)-2- piperidinecarboxamide) JG-7 B(2S,2′S)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(1-(cyclopropylcarbonyl)-2- pyrrolidinecarboxamide) JG-8 B(2S,2′S)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(1-propionyl-2-pyrrolidinecarboxamide) JG-9 B(2S,2′S)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(1-(cyclobutylcarbonyl)-2- pyrrolidinecarboxamide) JG-10 B(2S,2′S)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(1-isonicotinoyl-2- pyrrolidinecarboxamide) JG-11 A(2S,2′S)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(1-acetyl-2-pyrrolidinecarboxamide) JG-12 C(2S,2′S)-N,N′-(1,3-oxazole-2,5-diyldi-4,1- phenylene)bis(3-methyl-2-((phenylacetyl)amino)butanamide) JG-13 B(2S,2′S)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(4-(methylsulfanyl)-2- ((phenylacetyl)amino)butanamide)JG-14 B (2R,2′R)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(3-(methylsulfanyl)-2- ((phenylacetyl)amino)propanamide)JG-15 B (2S,2′S)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(4-methoxy-2- ((phenylacetyl)amino)butanamide) JG-16 B(2S,2′S)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(3-tert-butoxy-2- ((phenylacetyl)amino)propanamide) JG-17 B(2S,2′S)-N,N′-(4,4′-(oxazole-2,5-diyl)bis(4,1-phenylene))bis(2-(2-phenylacetamido)hexanamide) JG-18 AN,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(1-((phenylacetyl)amino)cyclopropanecarboxamide) JG-19 0.009 C(2S,2′S)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(1-((2S)-2-methoxy-2-phenylacetyl)-2-pyrrolidinecarboxamide) JG-20 C(2S,2′S)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(1-((2S)-2-hydroxy-2-phenylacetyl)-2-pyrrolidinecarboxamide) JG-21 D1,3-oxazole-2,5-diylbis(4,1-phenylenecarbamoyl(2S)-2,1-pyrrolidinediyl(1S)-2-oxo-1-phenyl-2,1-ethanediyl) diacetate JG-22<0.005 D (2S)-1-((2S)-2-hydroxy-2-phenylpropanoyl)-N-(4-(2-(4-((((2S)-1-(2-hydroxy-2-phenylpropanoyl)-2-pyrrolidinyl)carbonyl)amino)phenyl)-1,3-oxazol-5-yl)phenyl)-2-pyrrolidinecarboxamide JG-23 D(2S,2′S)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(1-((2R)-2-hydroxy-2-phenylacetyl)-2-pyrrolidinecarboxamide) JG-24 D1,3-oxazole-2,5-diylbis(4,1-phenylenecarbamoyl(2S)-2,1-pyrrolidinediyl(1R)-2-oxo-1-phenyl-2,1-ethanediyl) diacetate JG-25 C(2S,2′S)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(1-((2R)-2-methoxy-2-phenylacetyl)-2-pyrrolidinecarboxamide) JG-26 D(2S,2′S)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(1-((2R)-2-(2-chlorophenyl)-2-hydroxyacetyl)-2-pyrrolidinecarboxamide) JG-27 C(2S,2′S)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(1-(oxo(phenyl)acetyl)-2- pyrrolidinecarboxamide) JG-28 B(2S,2′S)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(1-(1-benzofuran-2-ylcarbonyl)-2- pyrrolidinecarboxamide)JG-29 B (2S,2′S)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(1-(1,3-benzothiazol-2-ylcarbonyl)-2-pyrrolidinecarboxamide) JG-30 C(2S,2′S)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(1-(2,1-benzisoxazol-3-ylcarbonyl)-2-pyrrolidinecarboxamide) JG-31 C(2S,2′S)-N,N′-(1H-pyrazole-3,5-diyldi-4,1-phenylene)bis(1-(oxo(phenyl)acetyl)-2- pyrrolidinecarboxamide) JG-32 D(2S,2′S)-N,N′-(1H-pyrazole-3,5-diyldi-4,1-phenylene)bis(1-((2R)-2-hydroxy-2-phenylacetyl)-2-pyrrolidinecarboxamide) JG-33 C(2S,2′S)-N,N′-(1H-pyrazole-3,5-diyldi-4,1-phenylene)bis(1-((2S)-2-hydroxy-2-phenylacetyl)-2-pyrrolidinecarboxamide) JG-34 D1H-pyrazole-3,5-diylbis(4,1-phenylenecarbamoyl(2S)-2,1-pyrrolidinediyl(1S)-2-oxo-1-phenyl-2,1-ethanediyl) diacetate JG-35<0.005 D 1H-pyrazole-3,5-diylbis(4,1-phenylenecarbamoyl(2S)-2,1-pyrrolidinediyl(1R)-2-oxo-1-phenyl-2,1-ethanediyl) diacetate JG-36 D(2S,2′S)-N,N′-(1H-pyrazole-3,5-diyldi-4,1-phenylene)bis(1-((2R)-2-(2-chlorophenyl)-2-hydroxyacetyl)-2-pyrrolidinecarboxamide) JG-37 D(2S,2′S)-N,N′-(1H-pyrazole-3,5-diyldi-4,1-phenylene)bis(1-((2R)-2-methoxy-2-phenylacetyl)-2-pyrrolidinecarboxamide) JG-38 D(2S,2′S)-N,N′-(1H-pyrazole-3,5-diyldi-4,1-phenylene)bis(1-((2S)-2-methoxy-2-phenylacetyl)-2-pyrrolidinecarboxamide) JG-39 <0.005 D(2S,2′S)-N,N′-(1H-pyrazole-3,5-diyldi-4,1-phenylene)bis(1-((2S)-2-hydroxy-2-phenylpropanoyl)-2-pyrrolidinecarboxamide) JG-40 B(2S,2′S)-N,N′-(1H-pyrazole-3,5-diyldi-4,1-phenylene)bis(1-(1-benzofuran-2-ylcarbonyl)-2- pyrrolidinecarboxamide)JG-41 B (2S,2′S)-N,N′-(1H-pyrazole-3,5-diyldi-4,1-phenylene)bis(1-(1,3-benzothiazol-2-ylcarbonyl)-2-pyrrolidinecarboxamide) JG-42 D(2S,2′S)-N,N′-(1H-imidazole-4,5-diyldi-4,1-phenylene)bis(1-(oxo(phenyl)acetyl)-2- pyrrolidinecarboxamide) JG-43 D(2S,2′S)-N,N′-(1H-imidazole-4,5-diyldi-4,1-phenylene)bis(1-((2R)-2-hydroxy-2-phenylacetyl)-2-pyrrolidinecarboxamide) JG-44 B(2S,2′S)-N,N′-(1H-imidazole-4,5-diyldi-4,1-phenylene)bis(1-((2S)-2-hydroxy-2-phenylacetyl)-2-pyrrolidinecarboxamide) JG-45 C(2S,2′S)-N,N′-(1H-imidazole-4,5-diyldi-4,1-phenylene)bis(1-((2S)-2-methoxy-2-phenylacetyl)-2-pyrrolidinecarboxamide) JG-46 D(2S,2′S)-N,N′-(1H-imidazole-4,5-diyldi-4,1-phenylene)bis(1-((2S)-2-hydroxy-2-phenylpropanoyl)-2-pyrrolidinecarboxamide) JG-47 C(2S,2′S)-N,N′-(1H-imidazole-4,5-diyldi-4,1-phenylene)bis(1-((2R)-2-hydroxy-2-phenylpropanoyl)-2-pyrrolidinecarboxamide) JG-48 2.34 A(2S,2′S)-N,N′-(1H-imidazole-4,5-diyldi-4,1-phenylene)bis(1-(1-isoquinolinylcarbonyl)-2- pyrrolidinecarboxamide)JG-49 A (2S,2′S)-N,N′-(1H-imidazole-4,5-diyldi-4,1-phenylene)bis(1-((3-chloro-1-isoquinolinyl)carbonyl)-2-pyrrolidinecarboxamide) JG-50 B(2S,2′S)-N,N′-(1H-imidazole-4,5-diyldi-4,1-phenylene)bis(1-((3-chloro-5-methoxy-1-isoquinolinyl)carbonyl)-2-pyrrolidinecarboxamide) JG-51 B(2S,2′S)-N,N′-(1H-imidazole-4,5-diyldi-4,1-phenylene)bis(1-(1-benzofuran-2-ylcarbonyl)-2- pyrrolidinecarboxamide)JG-52 B (2S,2′S)-N,N′-(1H-imidazole-4,5-diyldi-4,1-phenylene)bis(1-(1-benzofuran-5-ylcarbonyl)-2- pyrrolidinecarboxamide)JG-53 C (2S,2′S)-N,N′-(2,5-furandiyldi-4,1-phenylene)bis(1-((2R)-2-phenylpropanoyl)-2-pyrrolidinecarboxamide) JG-54 B dibenzyl(2S,2′S)-2,2′-(2,5-furandiylbis(4,1-phenylenecarbamoyl))di(1-pyrrolidinecarboxylate) JG-55 B(2S,2′S)-N,N′-(2,5-furandiyldi-4,1-phenylene)bis(1-acetyl-2-pyrrolidinecarboxamide) JG-56 <0.005 D(2S,2′S)-N,N′-(2,5-furandiyldi-4,1-phenylene)bis(1-((2R)-2-hydroxy-2-phenylacetyl)-2- pyrrolidinecarboxamide) JG-57 B(2S,2′S)-N,N′-(2,5-furandiyldi-4,1-phenylene)bis(1-((2R)-2-hydroxy-2-phenylacetyl)-2- pyrrolidinecarboxamide) JG-58 C(2S,2′S)-N,N′-(2,5-furandiyldi-4,1-phenylene)bis(1-((2R)-2-hydroxy-2-phenylpropanoyl)-2- pyrrolidinecarboxamide) JG-59 D(2S)-1-((2S)-2-hydroxy-2-phenylpropanoyl)-N-(4-(5-(4-((((2S)-1-(2-hydroxy-2-phenylpropanoyl)-2-pyrrolidinyl)carbonyl)amino)phenyl)-2-furyl)phenyl)-2-pyrrolidinecarboxamide JG-60 A(2S,2′S)-N,N′-(2,5-furandiyldi-4,1-phenylene)bis(1-((3-chloro-5-methoxy-1-isoquinolinyl)carbonyl)-2- pyrrolidinecarboxamide)JG-61 A (2S,2′S)-N,N′-(2,5-furandiyldi-4,1-phenylene)bis(1-((3-chloro-1-isoquinolinyl)carbonyl)-2- pyrrolidinecarboxamide) JG-62 B(2S,2′S)-N,N′-(2,5-furandiyldi-4,1-phenylene)bis(1-(1-isoquinolinylcarbonyl)-2-pyrrolidinecarboxamide) JG-63 D(2S,2′S)-N,N′-(2,5-furandiyldi-4,1-phenylene)bis(1-((2R)-2-(dimethylamino)-2-phenylacetyl)-2- pyrrolidinecarboxamide) JG-64C (2S)-1-((3-chloro-5-methoxy-1-isoquinolinyl)carbonyl)-N-(4-(5-(4-((((2S)-1-((2R)-2-hydroxy-2-phenylacetyl)-2-pyrrolidinyl)carbonyl)amino)phenyl)-2-furyl)phenyl)-2-pyrrolidinecarboxamide JG-65 D (2S)-1-((3-chloro-5-methoxy-1-isoquinolinyl)carbonyl)-N-(4-(5-(4-((((2S)-1-((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidinyl)carbonyl)amino)phenyl)-2-furyl)phenyl)-2-pyrrolidinecarboxamide JG-66 D(2S)-1-((2R)-2-(dimethylamino)-2-phenylacetyl)-N-(4-(5-(4-((((2S)-1-((2R)-2-hydroxy-2-phenylacetyl)-2-pyrrolidinyl)carbonyl)amino)phenyl)-2-furyl)phenyl)-2-pyrrolidinecarboxamide JG-67 0.0052 C(2S)-1-((2R)-2-acetamido-2-phenylacetyl)-N-(4-(5-(4-((((2S)-1-((3-chloro-5-methoxy-1- isoquinolinyl)carbonyl)-2-pyrrolidinyl)carbonyl)amino)phenyl)-2-furyl)phenyl)-2-pyrrolidinecarboxamide JG-68 B (2S)-1-((3-chloro-5-methoxy-1-isoquinolinyl)carbonyl)-N-(4-(5-(4-((((2S)-1-((2S)-2-hydroxy-2-phenylacetyl)-2-pyrrolidinyl)carbonyl)amino)phenyl)-2-furyl)phenyl)-2-pyrrolidinecarboxamide JG-69 D2,5-furandiylbis(4,1-phenylenecarbamoyl(2S)-2,1-pyrrolidinediyl(1R)-2-oxo-1-phenyl-2,1-ethanediyl) diacetate JG-70 B2,5-furandiylbis(4,1-phenylenecarbamoyl(2S)-2,1-pyrrolidinediyl(1S)-2-oxo-1-phenyl-2,1-ethanediyl) diacetate FY-1 B(2S,2′S)-N,N′-((1-methyl-1H-pyrazole-3,5-diyl)di-4,1-phenylene)bis(1-(phenylacetyl)-2- pyrrolidinecarboxamide) FY-2 A(2S,2′S)-N,N′-((1-methyl-1H-pyrazole-3,5-diyl)di-4,1-phenylene)bis(1-acetyl-2-pyrrolidinecarboxamide) FY-3 B dibenzyl(2S,2′S)-2,2′-((1-methyl-1H-pyrazole-3,5-diyl)bis(4,1-phenylenecarbamoyl))di(1- pyrrolidinecarboxylate) FY-4 A(2S,2′S)-N,N′-((1-methyl-1H-pyrazole-3,5-diyl)di-4,1-phenylene)bis(1-(cyclopropylcarbonyl)-2- pyrrolidinecarboxamide) FY-5 BN′,N′″-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(1-((3R)-1-((2R)-2-hydroxy-2-phenylacetyl)-3- pyrrolidinyl)urea) FY-6 BN′,N′″-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(1-((3R)-1-((2S)-2-hydroxy-2-phenylacetyl)-3- pyrrolidinyl)urea) FY-7 BN′,N′″-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(1-((3R)-1-(2-hydroxy-2-phenylpropanoyl)-3- pyrrolidinyl)urea) FY-8 BN′,N′″-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(1-((3R)-1-((2R)-2-(dimethylamino)-2-phenylacetyl)-3- pyrrolidinyl)urea)FY-9 C N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(2-((2R)-2-(dimethylamino)-2-phenylacetyl)-1- pyrazolidinecarboxamide) RK-1C dibenzyl (2S,2′S)-2,2′-(1,3,4-oxadiazole-2,5-diylbis(4,1-phenylenecarbamoyl))di(1- pyrrolidinecarboxylate) RK-2 Adibenzyl (2S,2′S)-2,2′-(1,3,4-oxadiazole-2,5-diylbis(4,1-phenylenecarbamoyl))bis(5-oxo-1- pyrrolidinecarboxylate)RK-3 B N,N′-(1,3,4-oxadiazole-2,5-diyldi-4,1-phenylene)bis(1-(phenylacetyl)-2-pyrrolidinecarboxamide) RK-4 B dibenzyl(2S,2′S)-2,2′-(1,3,4-oxadiazole-2,5-diylbis(4,1-phenylenecarbamoyl))di(1- piperidinecarboxylate) RK-5 Adibenzyl (2R,2′R)-2,2′-(1,3,4-oxadiazole-2,5-diylbis(4,1-phenylenecarbamoyl))di(1- piperidinecarboxylate) RK-6 B(2S,2′S)-N,N′-(1,3,4-oxadiazole-2,5-diyldi-4,1-phenylene)bis(1-(2-methoxybenzoyl)-2- pyrrolidinecarboxamide) RK-7 B(2S,2′S)-N,N′-(1,3,4-oxadiazole-2,5-diyldi-4,1-phenylene)bis(1-(3-methoxybenzoyl)-2- pyrrolidinecarboxamide) RK-8 1.85A (2S,2′S)-N,N′-(1,3,4-oxadiazole-2,5-diyldi-4,1-phenylene)bis(1-(2-ethoxybenzoyl)-2- pyrrolidinecarboxamide) RK-9 B(2S,2′S)-N,N′-(1,3,4-oxadiazole-2,5-diyldi-4,1-phenylene)bis(1-(2-ethylbenzoyl)-2- pyrrolidinecarboxamide) RK-10 A(2S,2′S)-N,N′-(1,3,4-oxadiazole-2,5-diyldi-4,1-phenylene)bis(1-(2-quinolinylcarbonyl)-2- pyrrolidinecarboxamide) RK-11B (2S,2′S)-N,N′-(1,3,4-oxadiazole-2,5-diyldi-4,1-phenylene)bis(1-(methoxy(phenyl)acetyl)-2- pyrrolidinecarboxamide) RK-123.96 A (2S,2′S)-N,N′-(1,3,4-oxadiazole-2,5-diyldi-4,1-phenylene)bis(1-((6-chloro-2-pyridinyl)carbonyl)-2-pyrrolidinecarboxamide) RK-13 B(2S,2′S)-N,N′-(1,3,4-oxadiazole-2,5-diyldi-4,1-phenylene)bis(1-(2-furoyl)-2-pyrrolidinecarboxamide) RK-14 B(2S,2′S)-N,N′-(1,3,4-oxadiazole-2,5-diyldi-4,1-phenylene)bis(1-((2S)-tetrahydro-2-furanylcarbonyl)-2-pyrrolidinecarboxamide) RK-15 A(2S,2′S)-N,N′-(1,3,4-oxadiazole-2,5-diyldi-4,1-phenylene)bis(1-((2R)-tetrahydro-2-furanylcarbonyl)-2-pyrrolidinecarboxamide) RK-16 <0.005 D(2S,2′S)-N,N′-(1,3,4-oxadiazole-2,5-diyldi-4,1-phenylene)bis(1-((2R)-2-hydroxy-2-phenylacetyl)-2-pyrrolidinecarboxamide) RK-17 B(2S,2′S)-N,N′-(1,3,4-oxadiazole-2,5-diyldi-4,1-phenylene)bis(1-((2S)-2-hydroxy-2-phenylacetyl)-2-pyrrolidinecarboxamide) RK-18 A(2S,2′S)-N,N′-(1,3,4-oxadiazole-2,5-diyldi-4,1-phenylene)bis(1-((3-chloro-1-isoquinolinyl)carbonyl)-2-pyrrolidinecarboxamide) RK-19 B(2S,2′S)-N,N′-(1,3,4-oxadiazole-2,5-diyldi-4,1- phenylene)bis(2-((methoxy(phenyl)acetyl)amino)propanamide) RK-20 AN,N′-(1,3,4-oxadiazole-2,5-diylbis(4,1-phenyleneimino((2S)-1-oxo-1,2-propanediyl)))bis(6-chloro-2-pyridinecarboxamide) RK-21 AN,N′-(1,3,4-oxadiazole-2,5-diylbis(4,1-phenyleneimino((2S)-1-oxo-1,2-propanediyl)))di(2- furamide) RK-22 BN,N′-(1,3,4-oxadiazole-2,5-diylbis(4,1-phenyleneimino((2S)-1-oxo-1,2-propanediyl)))bis(4-methoxy-2-quinolinecarboxamide) RK-23 B(2S,2′S)-N,N′-(1,3,4-oxadiazole-2,5-diyldi-4,1-phenylene)bis(2-((phenylacetyl)amino)propanamide) RK-24 B(2S,2′S)-N,N′-(1,3,4-oxadiazole-2,5-diyldi-4,1-phenylene)bis(2-(((2S)-2-hydroxy-2- phenylacetyl)amino)propanamide)RK-25 B (2R,2′R)-N,N′-(1,3,4-oxadiazole-2,5-diyldi-4,1-phenylene)bis(1-((6-fluoro-2-pyridinyl)carbonyl)-2-pyrrolidinecarboxamide) RK-26 A(3S,3′S)-N,N′-(1,3,4-oxadiazole-2,5-diyldi-4,1-phenylene)bis(1-((4-methoxy-2-quinolinyl)carbonyl)-3-piperidinecarboxamide) RK-27 B(2S,2′S)-N,N′-(1,3,4-oxadiazole-2,5-diyldi-4,1-phenylene)bis(1-((4-chloro-2-pyridinyl)carbonyl)-2-pyrrolidinecarboxamide) RK-28 0.003 D(2S,2′S)-N,N′-(1,3,4-oxadiazole-2,5-diyldi-4,1-phenylene)bis(1-((2R)-2-hydroxy-2-phenylpropanoyl)-2-pyrrolidinecarboxamide) RK-29 AN,N′-(1,3,4-oxadiazole-2,5-diylbis(4,1-phenyleneimino((2S)-1-oxo-1,2-propanediyl)))bis(6-fluoro-2-pyridinecarboxamide) RK-30 B(2S,2′S)-N,N′-(1,3,4-oxadiazole-2,5-diylbis(4,1-phenyleneimino((2S)-1-oxo-1,2-propanediyl)))bis(2-hydroxy-2-phenylpropanamide) RK-31 B(2R,2′R)-N,N′-(1,3,4-oxadiazole-2,5-diylbis(4,1-phenyleneimino((2S)-1-oxo-1,2-propanediyl)))bis(2-hydroxy-2-phenylpropanamide) RK-32 B(2S,2′S)-N,N′-(1,3,4-oxadiazole-2,5-diyldi-4,1-phenylene)bis(1-((3-chloro-5-methoxy-1-isoquinolinyl)carbonyl)-2-pyrrolidinecarboxamide) RK-33 BN,N′-(1,3,4-oxadiazole-2,5-diylbis(4,1-phenyleneimino((2S)-1-oxo-1,2-propanediyl)))bis(3-chloro-5-methoxy-1-isoquinolinecarboxamide) RK-34 A(2S,2′S)-N,N′-(1,3,4-oxadiazole-2,5-diylbis(4,1-phenyleneimino((2S)-1-oxo-1,2-propanediyl)))ditetrahydro-2-furancarboxamide RK-35 A(2R,2′R)-N,N′-(1,3,4-oxadiazole-2,5-diylbis(4,1-phenyleneimino((2S)-1-oxo-1,2-propanediyl)))ditetrahydro-2-furancarboxamide RK-36 1.00 AN,N′-(1,3,4-oxadiazole-2,5-diylbis(4,1-phenyleneimino((2S)-1-oxo-1,2-propanediyl)))bis(3-chloro-1-isoquinolinecarboxamide) RK-37 AN,N′-(1,3,4-oxadiazole-2,5-diylbis(4,1-phenyleneimino((2S)-1-oxo-1,2-propanediyl)))bis(4-chloro-2-pyridinecarboxamide) RK-38 <0.005 D(2S,2′S)-N,N′-(1,3,4-oxadiazole-2,5-diyldi-4,1-phenylene)bis(2-(((2S)-2-(dimethylamino)-2-phenylacetyl)amino)propanamide) RK-39 <0.005 D(2S,2′S)-N,N′-(1,3,4-oxadiazole-2,5-diyldi-4,1-phenylene)bis(1-((2S)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidinecarboxamide) RK-40 A(2S,2′S)-N,N′-(1,3,4-oxadiazole-2,5-diyldi-4,1-phenylene)bis(1-(2-chloro-6-methoxyisonicotinoyl)-2-pyrrolidinecarboxamide) RK-41 A N,N′-(1,3,4-oxadiazole-2,5-diylbis(4,1-phenyleneimino((2S)-1-oxo-1,2-propanediyl)))bis(2-chloro-6-methoxyisonicotinamide) RK-42 A(2S,2′S)-N,N′-(1,3,4-oxadiazole-2,5-diyldi-4,1-phenylene)bis(1-((1-methyl-1H-indol-3-yl)carbonyl)-2-pyrrolidinecarboxamide) JR-1 B(2S,2′S)-N,N′-(2,5-oxazolediyldi-4,1-phenylene)bis[1-[2-(1-methyl-1H-indol-3-yl)-1,2-dioxoethyl]-2- pyrrolidinecarboxamide]JR-2 B (2S,2′S)-N,N′-(2,5-oxazolediyldi-4,1-phenylene)bis[1-(3,3,3-trifluoro-2-hydroxy-1-oxopropyl)-2- pyrrolidinecarboxamide] JR-3B (2S,2′S)-N,N′-(2,5-oxazolediyldi-4,1-phenylene)bis[1-[hydroxy(1-methyl-1H-imidazol-5-yl)acetyl]-2- pyrrolidinecarboxamide]JR-4 A (2S,2′S)-N,N′-(2,5-oxazolediyldi-4,1-phenylene)bis[1-[2-hydroxy-1-oxo-3-(3-pyridinyl)propyl]-2- pyrrolidinecarboxamide] JR-5B (2S,2′S)-N,N′-(2,5-oxazolediyldi-4,1-phenylene)bis[1-[2-hydroxy-3-(1H-indol-3-yl)-1-oxopropyl]-2- pyrrolidinecarboxamide]JR-6 <0.005 D (2S,2′S)-N,N′-(2,5-oxazolediyldi-4,1-phenylene)bis[1-(hydroxy-2-thienylacetyl)-2-pyrrolidinecarboxamide] JR-7 C(2S,2′S)-N,N′-(2,5-oxazolediyldi-4,1-phenylene)bis[1-(hydroxy-3-pyridinylacetyl)-2-pyrrolidinecarboxamide] JR-8 C(2S)-N,N′-(4,4′-(oxazole-2,5-diyl)bis(4,1-phenylene))bis(1-(3-(4-bromophenyl)-2-(dimethylamino)propanoyl)pyrrolidine-2-carboxamide) JR-9 B(2S,2′S)-N,N′-(2,5-oxazolediyldi-4,1-phenylene)bis[1-[(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)acetyl]-2-pyrrolidinecarboxamide] JR-10 A(2S,2′S)-N,N′-(2,5-oxazolediyldi-4,1-phenylene)bis[1-[2-(3-ethyl-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)-1-oxopropyl]-2-pyrrolidinecarboxamide] JR-11 B(2S,2′S)-N,N′-(2,5-oxazolediyldi-4,1-phenylene)bis[1-[(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)phenylacetyl]-2-pyrrolidinecarboxamide] JR-12 B(2S)-N,N′-(4,4′-(oxazole-2,5-diyl)bis(4,1-phenylene))bis(1-(2-(dimethylamino)-3-(1H-1,2,4-triazol-1-yl)propanoyl)pyrrolidine-2-carboxamide) JR-13 0.112 B(S,S,2S)-N,N′-(4,4′-(oxazole-2,5-diyl)bis(4,1-phenylene))bis(1-((2S,3S)-2-(dimethylamino)-3-hydroxy-3-phenylpropanoyl)pyrrolidine-2- carboxamide) JR-14 A(S,R,2S)-N,N′-(4,4′-(oxazole-2,5-diyl)bis(4,1-phenylene))bis(1-((2S,3R)-2-(dimethylamino)-3-hydroxy-3-phenylpropanoyl)pyrrolidine-2- carboxamide) JR-15 C(S,S,2S)-N,N′-(4,4′-(oxazole-2,5-diyl)bis(4,1-phenylene))bis(1-((2S,3S)-2-(dimethylamino)-3-hydroxy-3-(thiophen-3-yl)propanoyl)pyrrolidine-2- carboxamide) JR-16 A(S,R,2S)-N,N′-(4,4′-(oxazole-2,5-diyl)bis(4,1-phenylene))bis(1-((2S,3R)-2-(dimethylamino)-3-hydroxy-3-(thiophen-3-yl)propanoyl)pyrrolidine-2- carboxamide) JR-17 A(2S,2′S)-N,N′-(2,5-oxazolediyldi-4,1-phenylene)bis[1-[(hexahydro-5-oxopyrrolo[2,1-b]thiazol-3-yl)carbonyl]-2-pyrrolidinecarboxamide] JR-18 A(2S,2′S)-N,N′-(2,5-oxazolediyldi-4,1-phenylene)bis[1-[2-(octahydro-1,3-dioxo-4,7-methano-2H-isoindol-2-yl)-1-oxopropyl]-2-pyrrolidinecarboxamide] JR-19 B(2S,2′S)-N,N′-(2,5-oxazolediyldi-4,1-phenylene)bis[1-[2-(1,3,3a,4,7,7a-hexahydro-1,3-dioxo-4,7-methano-2H-isoindol-2-yl)-3-methyl-1-oxobutyl]-2- pyrrolidinecarboxamide] JR-20A (2S,2′S)-N,N′-(2,5-oxazolediyldi-4,1-phenylene)bis[1-[[(4S)-2-oxo-4-phenyl-3-oxazolidinyl]acetyl]-2- pyrrolidinecarboxamide]JR-21 A (2S,2′S)-N,N′-(2,5-oxazolediyldi-4,1-phenylene)bis[1-[[(4R)-2-oxo-4-phenyl-3-oxazolidinyl]acetyl]-2- pyrrolidinecarboxamide]JR-22 1.72 A (2S,2′S)-N,N′-(2,5-oxazolediyldi-4,1-phenylene)bis[1-[(2,4-dioxo-5-phenyl-3-oxazolidinyl)acetyl]-2- pyrrolidinecarboxamide]XY-1 B (2S,2′S)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(1-(2-thienylcarbonyl)-2- pyrrolidinecarboxamide) XY-2 B(2S,2′S)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(1-((1-cyanocyclopropyl)carbonyl)-2-pyrrolidinecarboxamide) XY-3 0.321 B(2S,2′S)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(1-((3-methoxyphenyl)acetyl)-2- pyrrolidinecarboxamide)XY-4 B (2S,2′S)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(1-(3-pyridinylcarbonyl)-2- pyrrolidinecarboxamide) XY-5 A(2S,2′S)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(1-((dimethylamino)acetyl)-2- pyrrolidinecarboxamide) XY-6A (2S,2′S)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(1-(2-pyridinylcarbonyl)-2- pyrrolidinecarboxamide) XY-7 B(2S,2′S)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(1-(3,5-difluorobenzoyl)-2- pyrrolidinecarboxamide) XY-8 A(2S,2′S)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(1-((2-methoxyethoxy)acetyl)-2- pyrrolidinecarboxamide)XY-9 B (2S,2′S)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(1-(2-methylpentanoyl)-2- pyrrolidinecarboxamide) XY-10 B(2S,2′S)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(1-(2-fluorobenzoyl)-2- pyrrolidinecarboxamide) XY-11 B(2S,2′S)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(1-((5-methoxy-1H-indol-3-yl)acetyl)-2-pyrrolidinecarboxamide) XY-12 0.22 B(2S,2′S)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(1-(2-(3-chlorophenoxy)propanoyl)-2-pyrrolidinecarboxamide) XY-13 4.54 A 4,4′-(1,3-oxazole-2,5-diylbis(4,1-phenylenecarbamoyl(2S)-2,1-pyrrolidinediyl))bis(4- oxobutanoic acid)XY-14 A (2S)-1-(1H-imidazol-4-ylacetyl)-N-(4-(2-(4-((((2S)-1-(1H-imidazol-5-ylacetyl)-2-pyrrolidinyl)carbonyl)amino)phenyl)-1,3-oxazol-5-yl)phenyl)-2-pyrrolidinecarboxamide (non-preferred name) XY-15 B(2S,2′S)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(1-(cyclohexylcarbonyl)-2- pyrrolidinecarboxamide) XY-16 B(2S,2′S)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(1-((2-methylcyclopropyl)carbonyl)-2-pyrrolidinecarboxamide) XY-17 B(2S,2′S)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(1-(3-chloro-2,2-dimethylpropanoyl)-2-pyrrolidinecarboxamide) XY-18 C(2S,2′S)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(1-(tetrahydro-3-furanylcarbonyl)-2-pyrrolidinecarboxamide) XY-19 A(2S,2′S)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(1-(2,2-dimethylpentanoyl)-2- pyrrolidinecarboxamide) XY-200.062 C (2S,2′S)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(1-((2R)-2-phenylbutanoyl)-2- pyrrolidinecarboxamide) XY-21A (2S,2′S)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(1-((1-methyl-1H-imidazol-2-yl)carbonyl)-2-pyrrolidinecarboxamide) XY-22 <0.0045 D(2S,2′S)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(1-((4-fluorophenyl)acetyl)-2- pyrrolidinecarboxamide)XY-23 B (2S,2′S)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(1-((1-acetyl-4-piperidinyl)carbonyl)-2-pyrrolidinecarboxamide) XY-24 B(2S,2′S)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(1-(cyclopropylacetyl)-2- pyrrolidinecarboxamide) XY-25 A(2S,2′S)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(1-((3-chloro-2-thienyl)carbonyl)-2-pyrrolidinecarboxamide) XY-26 A(2S,2′S)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(1-((2R)-2-methoxy-2-phenylacetyl)-2-pyrrolidinecarboxamide) XY-27 B(2S,2′S)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(1-(4,5-dimethyl-2-furoyl)-2- pyrrolidinecarboxamide) XY-28B (2S,2′S)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(1-((3,5-dimethyl-4-isoxazolyl)carbonyl)-2-pyrrolidinecarboxamide) XY-29 B(2S,2′S)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(1-(4-methoxybenzoyl)-2- pyrrolidinecarboxamide) XY-30 A(2S,2′S)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(1-((2-methyl-3-pyridinyl)carbonyl)-2-pyrrolidinecarboxamide) XY-31 0.054 C(2S,2′S)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(1-(tetrahydro-2-furanylcarbonyl)-2-pyrrolidinecarboxamide) XY-32 C(2S,2′S)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(1-((2R)-tetrahydro-2-furanylcarbonyl)-2-pyrrolidinecarboxamide) XY-33 A(2S,2′S)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(1-(1H-pyrrol-2-ylcarbonyl)-2- pyrrolidinecarboxamide)XY-34 B (2S,2′S)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(1-(2,5-dimethyl-3-furoyl)-2- pyrrolidinecarboxamide) XY-35B (2S,2′S)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(1-((2-methoxyphenyl)acetyl)-2- pyrrolidinecarboxamide)XY-36 B (2S,2′S)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(1-(1,3-benzodioxol-5-ylcarbonyl)-2-pyrrolidinecarboxamide) XY-37 B(2S,2′S)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(1-(2-furoyl)-2-pyrrolidinecarboxamide) XY-38 C(2S,2′S)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(1-(3-furoyl)-2-pyrrolidinecarboxamide) XY-39 B(2S,2′S)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(1-((1-methylcyclopropyl)carbonyl)-2-pyrrolidinecarboxamide) XY-40 B(2S,2′S)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(1-((1-methyl-1H-pyrrol-2-yl)acetyl)-2-pyrrolidinecarboxamide) XY-41 A(2S,2′S)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(1-(1-piperidinylacetyl)-2- pyrrolidinecarboxamide) XY-42 A(2S,2′S)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(1-((1-methyl-1H-imidazol-4-yl)acetyl)-2-pyrrolidinecarboxamide) XY-43 A(2S,2′S)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(1-(2,5-dimethylbenzoyl)-2- pyrrolidinecarboxamide) XY-44 A(2S,4R,2′S,4′R)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(1-(cyclopropylacetyl)-4-hydroxy-2- pyrrolidinecarboxamide)XY-45 A (2S,4R,2′S,4′R)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(4-hydroxy-1-(3-pyridinylacetyl)-2- pyrrolidinecarboxamide)XY-46 B (2S,4R,2′S,4′R)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(1-(cyclobutylcarbonyl)-4-hydroxy-2-pyrrolidinecarboxamide) XY-47 0.564 B(2S,4R,2′S,4′R)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(1-(2-ethylbenzoyl)-4-hydroxy-2- pyrrolidinecarboxamide)XY-48 A (2S,4R,2′S,4′R)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(1-(cyclohexylcarbonyl)-4-hydroxy-2-pyrrolidinecarboxamide) XY-49 C(2S,4R,2′S,4′R)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(4-hydroxy-1-(methoxy(phenyl)acetyl)-2-pyrrolidinecarboxamide) XY-50 A(2S,4R,2′S,4′R)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(4-hydroxy-1-((2R)-tetrahydro-2-furanylcarbonyl)-2-pyrrolidinecarboxamide) XY-51 B(2S,4R,2′S,4′R)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(4-hydroxy-1-((3-methylphenyl)acetyl)-2-pyrrolidinecarboxamide) XY-52 A(2S,4R,2′S,4′R)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(4-hydroxy-1-((3-methyl-5-isoxazolyl)acetyl)-2-pyrrolidinecarboxamide) XY-53 8.06 A(2S,4R,2′S,4′R)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(1-((3,5-dimethyl-4-isoxazolyl)carbonyl)-4-hydroxy-2-pyrrolidinecarboxamide) XY-54 A(2S,4R,2′S,4′R)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(4-hydroxy-1-(2-thienylcarbonyl)-2- pyrrolidinecarboxamide)XY-55 B (2S,4R,2′S,4′R)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(4-hydroxy-1-((3-methoxyphenyl)acetyl)-2-pyrrolidinecarboxamide) XY-56 B(2S,4R,2′S,4′R)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(1-benzoyl-4-hydroxy-2- pyrrolidinecarboxamide) XY-57 A(2S,4R,2′S,4′R)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(1-(cyclopropylcarbonyl)-4-hydroxy-2-pyrrolidinecarboxamide) XY-58 B(2S,4R,2′S,4′R)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(4-hydroxy-1-(2-pyridinylacetyl)-2- pyrrolidinecarboxamide)XY-59 A dibenzyl (2S,4R,2′S,4′R)-2,2′-(1,3-oxazole-2,5-diylbis(4,1-phenylenecarbamoyl))bis(4-tert-butoxy-1-pyrrolidinecarboxylate) XY-60 A(2S,4R,2′S,4′R)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(4-tert-butoxy-2-pyrrolidinecarboxamide) XY-61 B(2S,4R,2′S,4′R)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(4-tert-butoxy-1-(cyclopropylacetyl)-2-pyrrolidinecarboxamide) XY-62 C(2S,4R,2′S,4′R)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(4-tert-butoxy-1-(3-pyridinylacetyl)-2-pyrrolidinecarboxamide) XY-63 B(2S,4R,2′S,4′R)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(4-tert-butoxy-1-(2,2-dimethylpropanoyl)-2-pyrrolidinecarboxamide) XY-64 A(2S,4R,2′S,4′R)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(4-tert-butoxy-1-(cyclobutylcarbonyl)-2-pyrrolidinecarboxamide) XY-65 A(2S,4R,2′S,4′R)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(4-tert-butoxy-1-(2-ethylbenzoyl)-2-pyrrolidinecarboxamide) XY-66 A(2S,4R,2′S,4′R)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(4-tert-butoxy-1-(cyclohexylcarbonyl)-2-pyrrolidinecarboxamide) XY-67 C(2S,4R,2′S,4′R)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(4-tert-butoxy-1-(methoxy(phenyl)acetyl)-2-pyrrolidinecarboxamide) XY-68 B(2S,4R,2′S,4′R)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(4-tert-butoxy-1-((2R)-tetrahydro-2-furanylcarbonyl)-2-pyrrolidinecarboxamide) XY-69 B(2S,4R,2′S,4′R)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(4-tert-butoxy-1-((3-methylphenyl)acetyl)-2-pyrrolidinecarboxamide) XY-70 C(2S,4R,2′S,4′R)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(4-tert-butoxy-1-((3-methyl-5-isoxazolyl)acetyl)-2-pyrrolidinecarboxamide) XY-71 A(2S,4R,2′S,4′R)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(4-tert-butoxy-1-((1-methyl-1H-pyrrol-2-yl)carbonyl)-2-pyrrolidinecarboxamide) XY-72 B(2S,4R,2′S,4′R)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(4-tert-butoxy-1-((3,5-dimethyl-4-isoxazolyl)carbonyl)-2-pyrrolidinecarboxamide) XY-73 A(2S,4R,2′S,4′R)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(1-benzoyl-4-tert-butoxy-2- pyrrolidinecarboxamide) XY-74 B(2S,4R,2′S,4′R)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(4-tert-butoxy-1-(cyclopropylcarbonyl)-2-pyrrolidinecarboxamide) XY-75 C(2S,4R,2′S,4′R)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(4-tert-butoxy-1-(2-pyridinylacetyl)-2-pyrrolidinecarboxamide) XY-76 A(2S,4R,2′S,4′R)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(4-tert-butoxy-1-(2-thienylcarbonyl)-2-pyrrolidinecarboxamide) XY-77 B(2S,4R,2′S,4′R)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(4-tert-butoxy-1-((3-methoxyphenyl)acetyl)-2-pyrrolidinecarboxamide)

The compounds of the present disclosure may inhibit HCV by mechanisms inaddition to or other than NS5A inhibition. In one embodiment thecompounds of the present disclosure inhibit HCV replicon and in anotherembodiment the compounds of the present disclosure inhibit NS5A.

It will be evident to one skilled in the art that the present disclosureis not limited to the foregoing illustrative examples, and that it canbe embodied in other specific forms without departing from the essentialattributes thereof. It is therefore desired that the examples beconsidered in all respects as illustrative and not restrictive,reference being made to the appended claims, rather than to theforegoing examples, and all changes which come within the meaning andrange of equivalency of the claims are therefore intended to be embracedtherein.

What is claimed is:
 1. A compound of Formula (I):

or a stereoisomer or a pharmaceutically acceptable salt thereof,wherein: Q¹, Q², Q³, Q⁴, Q⁵, Q⁶, Q⁷, and Q⁸ are each CR^(w); whereineach R^(w) is independently selected from hydrogen, C₁₋₆ alkoxy, C₁₋₄alkyl, and halo; L is a five-membered heterocyclyl group selected fromthe group consisting of

 wherein R^(x) at each occurrence is independently hydrogen, halogen, orC₁₋₄ alkyl optionally substituted by —C(O)OR³ or —NMe₂, wherein R^(y) ateach occurrence is independently hydrogen or C₁₋₄ alkyl, and wherein R³is hydrogen or C₁₋₄ alkyl; one of R¹ and R² is selected from C₁₋₆alkoxy, —NHR^(p), and alkyl, wherein said alkyl is optionallysubstituted by one, two, or three substituents independently selectedfrom aryl, alkenyl, cycloalkyl, heterocyclyl, heteroaryl, —OSi(R^(q))₃,—OR⁴, —SR⁵, —C(O)OR⁶, —NHC(O)R⁷, —NR^(a)R^(b), and —C(O)NR^(c)R^(d); andthe other is selected from heteroaryl, heterocyclyl, C₁₋₆ alkoxy,—NHR^(p), and alkyl, wherein said alkyl is optionally substituted byone, two, or three substituents independently selected from aryl,alkenyl, cycloalkyl, heterocyclyl, heteroaryl, —OSi(R^(q))₃, —OR⁴, —SR⁵,—C(O)OR⁶, —NHC(O)R⁷, —NR^(a)R^(b), and —C(O)NR^(c)R^(d); wherein R^(p)is heterocyclyl, wheren R^(q) at each occurrence is independently C₁₋₄alkyl or phenyl, wherein any said aryl or heteroaryl may optionally besubstituted with one or more substituents independently selected fromC₁₋₄ alkyl, C₁₋₄ haloalkyl, arylalkyl, heterocyclyl, heterocyclylalkyl,halogen, cyano, nitro, —OR⁴, —C(O)OR⁶, —NR^(a)R^(b), (NR^(a)R^(b))alkyl,and —OP(O)(OH)(OR⁵), and wherein any said cycloalkyl or heterocyclyl mayoptionally be fused onto an aromatic ring and may optionally besubstituted with one or more substituents independently selected fromC₁₋₄ alkyl, halogen, aryl, arylalkyl, heteroarylalkyl, fusedcyclopropyl, —NR^(a)R^(b), oxo, —OR⁴, —C(O)OR⁶, and —C(O)R⁷; R⁴ ishydrogen, C₁₋₆ alkyl, or benzyl; R⁵ is hydrogen or C₁₋₄ alkyl; R⁶ ateach occurrence is independently C₁₋₆ alkyl, aryl, benzyl, orheteroaryl; R⁷ at each occurrence is independently selected from —OR⁸,C₁₋₆ alkyl, C₁₋₆ haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl,and -L¹-R¹¹, wherein said aryl and heteroaryl may optionally besubstituted by one or more substituents independently selected from C₁₋₄alkyl, halogen, —OR⁹, and —NR^(a)R^(b), and wherein said cycloalkyl andheterocyclyl may optionally be substituted by one or more substituentsindependently selected from C₁₋₄ alkyl, —C(O)OR¹⁰, fused cyclopropyl,cyano, oxo, phenyl, —NR^(a)R^(b), -L¹-R¹¹, C(O)R¹¹, and —C(O)-L¹-R¹¹; R⁸is C₁₋₆ alkyl, phenyl optionally substituted with a halogen, arylalkyl,—(C₁₋₃ alkylene)-C(O)OR¹⁰, or —(C₁₋₃ alkylene)-O—(C₁₋₃ alkylene); R⁹ ishydrogen, C₁₋₆ alkyl, or C₁₋₄ haloalkyl; R¹⁰ is hydrogen, C₁₋₆ alkyl,phenyl, or benzyl; L¹ is C₁₋₂ alkylene optionally substituted by one ortwo substituents independently selected from C₁₋₄ alkyl, —OR¹²,—OC(O)R¹³, —NR^(a)R^(b), phenyl, and oxo; R¹¹ is C₁₋₆ alkyl, C₁₋₄haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —OR⁸, or—NR^(a)R^(b), wherein said aryl or heteroaryl may optionally besubstituted by one or more substituents independently selected from C₁₋₄alkyl, halogen, —OR⁹, nitro, cyano, and —NR^(a)R^(b), and wherein saidcycloalkyl or heterocyclyl may optionally be substituted by one or moresubstituents independently selected from C₁₋₄ alkyl, benzyl, phenyl,halogen, —OR⁹, oxo, fused cyclopropyl, —NR^(a)R^(b), —C(O)R¹⁰, and—C(O)OR¹⁰; R¹² is hydrogen, C₁₋₄ alkyl, aryl, or heteroaryl, whereinsaid aryl or heteroaryl may optionally be substituted by one or moresubstituents independently selected from C₁₋₄ alkyl, halogen, and —OR⁹;R¹³ is C₁₋₄ alkyl or aryl; R^(a) and R^(b) are independently selectedfrom hydrogen, C₁₋₆ alkyl, cycloalkyl, arylalkyl, heteroaryl,heterocyclyl, —C(O)R¹⁴, —C(O)OR¹⁵, —C(O)NR^(c)R^(d), and(NR^(c)R^(d))alkyl, or alternatively, R^(a) and R^(b), together with thenitrogen atom to which they are attached, form a five- or six-memberedring or bridged bicyclic ring structure, wherein said five- orsix-membered ring or bridged bicyclic ring structure optionally maycontain one or two additional heteroatoms independently selected fromnitrogen, oxygen, and sulfur and may contain one, two, or threesubstituents independently selected from C₁₋₆ alkyl, C₁₋₄ haloalkyl,aryl, halogen, and —OR⁹; R^(c) and R^(d) are independently selected fromhydrogen, C₁₋₄ alkyl, benzyl, and cycloalkyl; R¹⁴ is C₁₋₄ alkyl,arylalkyl, aryl, or heteroaryl, each optionally substituted by one, twoor three substituents independently selected from C₁₋₄ alkyl, halogen,and —OR⁹; and R¹⁵ is C₁₋₆ alkyl, arylalkyl, or C₁₋₄ haloalkyl.
 2. Thecompound of claim 1, or a stereoisomer or a pharmaceutically acceptablesalt thereof, wherein one of R¹ and R² is

and the other is selected from the group consisting of:

wherein: n is 0, 1, 2, or 3; R¹⁶ at each occurrence is independentlyC₁₋₄ alkyl, —OR⁴, or oxo; R¹⁷ at each occurrence is independentlyhydrogen or —C(O)R⁷, wherein R⁷ is defined as in claim 1; R¹⁸ is C₁₋₆alkyl optionally substituted by —OR⁴ or —SR⁵; R⁴ is hydrogen or C₁₋₆alkyl; and R⁵ is C₁₋₄ alkyl.
 3. The compound of claim 2, or astereoisomer or a pharmaceutically acceptable salt thereof, wherein R⁷at each occurrence is independently selected from the group consistingof —OCH₂Ph, —OC(CH₃)₃, methyl, ethyl, isopropyl, —CH₂Ph, cyclopropyl,cyclobutyl, phenyl,


4. The compound of claim 1, further characterized by formula (Ia):

or a stereoisomer or a pharmaceutically acceptable salt thereof,wherein: R^(x) is hydrogen, methyl, —CH₂C(O)OR³, or —CH₂NMe₂, wherein R³is hydrogen or C₁₋₄ alkyl; one of R¹ and R² is

and the other is selected from

R¹⁷ at each occurrence is independently hydrogen or —C(O)R⁷; R⁷ at eachoccurrence is independently —OR⁸ or benzyl; and R⁸ is C₁₋₄ alkyl orbenzyl.
 5. The compound of claim 1, further characterized by formula(Ib):

or a stereoisomer or a pharmaceutically acceptable salt thereof,wherein: R^(x) is hydrogen or C₁₋₄ alkyl; one of R¹ and R² is

and the other is selected from:

wherein: R¹⁶ is hydrogen, OH, or —OR⁴, wherein R⁴ is hydrogen or C₁₋₄alkyl; R¹⁷ at each occurrence is independently hydrogen or —C(O)R⁷; R⁷at each occurrence is independently selected from —OR⁸, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₆ cycloalkyl, heterocyclyl, aryl, heteroaryl, and -L¹-R¹¹,wherein said aryl and heteroaryl may optionally be substituted by one,two, or three substituents independently selected from C₁₋₄ alkyl,halogen, —OR⁹, and —NR^(a)R^(b), and wherein said cycloalkyl andheterocyclyl may optionally be substituted by one, two, or threesubstituents independently selected from C₁₋₄ alkyl, —C(O)OR¹⁰, fusedcyclopropyl, phenyl, oxo, —NR^(a)R^(b), -L¹-R¹¹, —C(O)R¹¹, and—C(O)-L¹-R¹¹; R⁸ is C ₁₋₄ alkyl or benzyl; R⁹ is hydrogen or C₁₋₄ alkyl;R¹⁰ is C₁₋₄ alkyl, phenyl, or benzyl; L¹ is C₁₋₂ alkylene optionallysubstituted by one or two substituents independently selected from C₁₋₄alkyl, —OR¹², —OC(O)R¹³, —NR^(a)R^(b), phenyl, and oxo; R¹¹ is C₁₋₄alkyl, C₁₋₄ haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or—NR^(a)R^(b), wherein said aryl or heteroaryl may optionally besubstituted by one, two, or three substituents independently selectedfrom C₁₋₄ alkyl, halogen, —OR⁹, and —NR^(a)R^(b), and wherein saidcycloalkyl or heterocyclyl may optionally be substituted by one, two, orthree substituents independently selected from C₁₋₄ alkyl, benzyl,phenyl, halogen, —OR⁹, oxo, fused cyclopropyl, —NR^(a)R^(b), —C(O)R¹⁰,and —C(O)OR¹⁰; R¹² is hydrogen, C₁₋₄ alkyl, aryl, or heteroaryl, whereinsaid aryl or heteroaryl may optionally be substituted by one or moresubstituents independently selected from C₁₋₄ alkyl, halogen, and —OR⁹;R¹³ is C₁₋₄ alkyl; R^(a) and R^(b) are independently selected fromhydrogen, C₁₋₄ alkyl, —C(O)R¹⁴, or alternatively, R^(a) and R^(b),together with the nitrogen atom to which they are attached, form a five-or six-membered ring, wherein said five- or six-membered ring optionallymay contain one additional heteroatom selected from nitrogen, oxygen,and sulfur and may contain one, two, or three substituents independentlyselected from C₁₋₄ alkyl, C₁₋₄ haloalkyl, aryl, halogen, and —OR⁹; R¹⁴is C₁₋₄ alkyl; R^(17a) is heteroarylalkyl; and R¹⁸ is C₁₋₄ alkyloptionally substituted by —OR⁴ or —SR⁵, wherein R⁴ and R⁵ are eachindependently C₁₋₄ alkyl.
 6. The compound of claim 5, or a stereoisomeror a pharmaceutically acceptable salt thereof, wherein: R^(x) ishydrogen; R⁷ is selected from the group consisting of —OCH₂Ph,—OC(CH₃)₃, methyl, ethyl, —CH₂Ph, cyclopropyl, cyclobutyl, phenyl,

and R^(17a) is


7. The compound of claim 1, further characterized by Formula (Id):

or a stereoisomer or a pharmaceutically acceptable salt thereof,wherein: R^(x) is hydrogen or C₁₋₄ alkyl; one of R¹ and R² is

and the other is selected from

R¹⁶ is hydrogen or —OH; R¹⁷ at each occurrence is independently hydrogenor —C(O)R⁷; R⁷ at each occurrence is independently selected from thegroup consisting of —OR⁸, C₁₋₄ alkyl, heteroaryl, and -L¹-R¹¹, whereinsaid heteroaryl may optionally be substituted by one, two, or threesubstituents independently selected from C₁₋₄ alkyl, halogen, and —OR⁹;R⁸ is C₁₋₄ alkyl or benzyl; R⁹ is hydrogen or C₁₋₄ alkyl; L¹ is C₁₋₂alkylene optionally substituted by one or two substituents independentlyselected from C₁₋₄ alkyl, —OR¹², and oxo; R¹¹ is aryl, C₁₋₄ alkyl,cycloalkyl, aryl, or heteroaryl, wherein said aryl or heteroaryl mayoptionally be substituted by one, two, or three substituentsindependently selected from C₁₋₄ alkyl, halogen, and —OR⁹; and R¹² ishydrogen or C₁₋₄ alkyl.
 8. The compound of claim 1, furthercharacterized by Formula (Ie):

or a pharmaceutically acceptable salt thereof, wherein: R^(x) and R^(y)are each independently hydrogen or C₁₋₄ alkyl; one of R¹ and R² is

and the other is selected from

R¹⁶ is hydrogen or —OR⁴, wherein R⁴ is hydrogen or C₁₋₄ alkyl; R¹⁷ ateach occurrence is independently hydrogen or —C(O)R⁷; R⁷ at eachoccurrence is independently selected from the group consisting of: —OR⁸,C₁₋₄ alkyl, aryl, C₃₋₆ cycloalkyl, heterocyclyl, heteroaryl, and-L^(l)-R¹¹, wherein said aryl and heteroaryl may optionally besubstituted by one, two, or three substituents independently selectedfrom C₁₋₄ alkyl, halogen, —OR⁹, and —NR^(a)R^(b), and wherein saidcycloalkyl and heterocyclyl may optionally be substituted by one or moresubstituents independently selected from C₁₋₄ alkyl, —OR⁹, —NR^(a)R^(b),and oxo; R⁸ is C₁₋₄ alkyl or benzyl; R⁹ is hydrogen or C₁₋₄ alkyl; L¹ isC₁₋₂ alkylene optionally substituted by one or two substituentsindependently selected from C₁₋₄ alkyl, —OR¹², —OC(O)R¹³, —NR^(a)R^(b),and oxo; R¹¹ is C₁₋₄ alkyl, cycloalkyl, aryl, or heteroaryl, whereinsaid aryl or heteroaryl may be optionally substituted by one, two, orthree substituents independently selected from C₁₋₄ alkyl, halogen,—OR⁹, and —NR^(a)R^(b), and wherein said cycloalkyl or heterocyclyl mayoptionally be substituted by one or more substituents independentlyselected from C₁₋₄ alkyl, halogen, —OR⁹, oxo, and —NR^(a)R^(b); R⁹ ishydrogen, C₁₋₄ alkyl, or C₁₋₄ haloalkyl; R¹⁰ is C₁₋₄ alkyl or benzyl;R¹² is hydrogen or C₁₋₄ alkyl; R¹³ is C₁₋₄ alkyl; R^(a) and R^(b) areeach independently hydrogen, C₁₋₄ alkyl, or —C(O)R¹⁴; and R¹⁴ is C₁₋₄alkyl.
 9. The compound of claim 1, or a stereoisomer or apharmaceutically acceptable salt thereof, wherein: R^(x) is hydrogen;R^(y) is hydrogen or C₁₋₄ alkyl; and R⁷ at each occurrence isindependently selected from the group consisting of —OCH₂Ph, —OC(CH₃)₃,methyl, ethyl, isopropyl, benzyl, cyclopropyl, cyclobutyl,


10. The compound of claim 1, further characterized by Formula (If):

or a stereoisomer or a pharmaceutically acceptable salt thereof,wherein: R^(x) is hydrogen or C₁₋₄ alkyl; one of R¹ and R² is

and the other is selected from

R¹⁶ is hydrogen or —OH; R¹⁷ at each occurrence is independently hydrogenor —C(O)R⁷; R⁷ at each occurrence is independently —OR⁸ or —CH₂Ph; andR⁸ is C₁₋₄ alkyl or benzyl.
 11. The compound of claim 1, furthercharacterized by Formula (Ig):

or a stereoisomer or a pharmaceutically acceptable salt thereof,wherein: R^(y) is hydrogen or C₁₋₄ alkyl; one of R¹ and R² is

and the other is selected from

R¹⁷ at each occurrence is independently hydrogen or —C(O)R⁷; and R⁷ ateach occurrence is independently —OR⁸; and R⁸ is C₁₋₄ alkyl or benzyl.12. The compound of claim 1, further characterized by Formula (Ih):

or a stereoisomer or a pharmaceutically acceptable salt thereof,wherein: R^(y) is hydrogen or C₁₋₄ alkyl; one of R¹ and R² is

and the other is selected from

R¹⁶ is hydrogen or —OH; and R¹⁷ at each occurrence is independentlyhydrogen or —C(O)R⁷; R⁷ at each occurrence is independently —OR⁸ orbenzyl; and R⁸ is C₁₋₄ alkyl or benzyl.
 13. A compound, or astereoisomer or a pharmaceutically acceptable salt thereof, selectedfrom the group consisting of:(4,5-bis(4-(((2S)-2-(((benzyloxy)carbonyl)amino)propanoyl)amino)phenyl)-1,3-oxazol-2-yl)aceticacid; ethyl(4,5-bis(4-(((2S)-2-(((benzyloxy)carbonyl)amino)propanoyl)amino)phenyl)-1,3-oxazol-2-yl)acetate;dibenzyl((2-methyl-1,3-oxazole-4,5-diyl)bis(4,1-phenyleneimino((2S)-1-oxo-1,2-propanediyl)))biscarbamate;dibenzyl(1H-imidazole-4,5-diylbis(4,1-phenyleneimino((2S)-1-oxo-1,2-propanediyl)))biscarbamate;(2S,2′S)-N,N′-(1H-imidazole-4,5-diyldi-4,1-phenylene)bis(2-((phenylacetyl)amino)propanamide);dibenzyl((5-oxo-1,5-dihydro-4H-1,2,4-triazole-3,4-diyl)bis(4,1-phenyleneimino((2S)-1-oxo-1,2-propanediyl)))biscarbamate; dibenzyl(4H-1,2,4-triazole-3,4-diylbis(4,1-phenyleneimino((2S)-1-oxo-1,2-propanediyl)))biscarbamate;dibenzyl(1H-1,2,3-triazole-4,5-diylbis(4,1-phenyleneimino((2S)-1-oxo-1,2-propanediyl)))biscarbamate;(2S,2′S)-N,N′-(1H-pyrazole-3,5-diyldi-4,1-phenylene)bis(2-(((2S)-2-hydroxy-2-phenylacetyl)amino)propanamide);(2S,2′S)-N,N′-(1H-pyrazole-3,5-diyldi-4,1-phenylene)bis(2-(((2R)-2-hydroxy-2-phenylacetyl)amino)propanamide);(2S ,2′S)-N,N′-(1H-pyrazole-3,5-diylbis(4,1-phenyleneimino((2S)-1-oxo-1,2-propanediyl)))bis(2-hydroxy-2-phenylpropanamide);(2R,2′R)-N,N′-(1H-pyrazole-3,5-diylbis(4,1-phenyleneimino((2S)-1-oxo-1,2-propanediyl)))bis(2-hydroxy-2-phenylpropanamide);N,N′-(1H-pyrazole-3,5-diylbis(4,1-phenyleneimino((2S)-1-oxo-1,2-propanediyl))) bis(3-chloro-1-naphthamide);N,N′-(1H-pyrazole-3,5-diylbis(4,1-phenyleneimino((2S)-1-oxo-1,2-propanediyl)))bis(3-chloro-1-isoquinolinecarboxamide);(2S ,2′S)-N,N′-(1,3 -oxazole-2,5 -diyldi-4,1-phenylene)bis(2-(((2S)-2-hydroxy-2-phenylacetyl)amino)propanamide); (2S,2′S)-N,N′-(1,3 -oxazole-2,5 -diyldi-4,1-phenylene)bis(2-(((2R)-2-hydroxy-2-phenylacetyl)amino)propanamide);((2S,2′S)-N,N′-(1,3-oxazole-2,5-diylbis(4,1-phenyleneimino((2S)-1-oxo-1,2-propanediyl)))bis(2-hydroxy-2-phenylpropanamide);(2R,2′R)-N,N′-(1,3-oxazole-2,5-diylbis(4,1-phenyleneimino((2S)-1-oxo-1,2-propanediyl)))bis(2-hydroxy-2-phenylpropanamide);dibenzyl(1,3-oxazole-2,5-diylbis(4,1-phenyleneimino((2S)-3-methyl-1-oxo-1,2-butanediyl)))biscarbamate;dibenzyl(1,3-oxazole-2,5-diylbis(4,1-phenyleneimino((2R)-3-methyl-1-oxo-1,2-butanediyl)))biscarbamate;(2S,2′S)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(3-methyl-2-((phenylacetyl)amino)butanamide);(2S,2′S)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(4-(methylsulfanyl)-2-((phenylacetyl)amino)butanamide);(2R,2′R)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(3-(methylsulfanyl)-2-((phenylacetyl)amino)propanamide);(2S,2′S)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(4-methoxy-2-((phenylacetyl)amino)butanamide);(2S,2′S)-N,N′-(1,3-oxazole-2,5-diyldi-4,1-phenylene)bis(3-tert-butoxy-2-((phenylacetyl)amino)propanamide);(2S,2′S)-N,N′-(4,4′-(oxazole-2,5-diyl)bis(4,1-phenylene))bis(2-(2-phenylacetamido)hexanamide);(2S,2′S)-N,N′-(1,3,4-oxadiazole-2,5-diyldi-4,1-phenylene)bis(2-((methoxy(phenyl)acetyl)amino)propanamide);N,N′-(1,3,4-oxadiazole-2,5-diylbis(4,1-phenyleneimino((2S)-1-oxo-1,2-propanediyl)))bis(6-chloro-2-pyridinecarboxamide);N,N′-(1,3,4-oxadiazole-2,5-diylbis(4,1-phenyleneimino((2S)-1-oxo-1,2-propanediyl)))di(2-furamide);N,N′-(1,3,4-oxadiazole-2,5-diylbis(4,1-phenyleneimino((2S)-1-oxo-1,2-propanediyl)))bis(4-methoxy-2-quinolinecarboxamide);(2S,2′S)-N,N′-(1,3,4-oxadiazole-2,5-diyldi-4,1-phenylene)bis(2-((phenylacetyl)amino)propanamide);(2S,2′S)-N,N′-(1,3,4-oxadiazole-2,5-diyldi-4,1-phenylene)bis(2-(((2S)-2-hydroxy-2-phenylacetyl)amino)propanamide);N,N′-(1,3,4-oxadiazole-2,5-diylbis(4,1-phenyleneimino((2S)-1-oxo-1,2-propanediyl)))bis(6-fluoro-2-pyridinecarboxamide);(2S,2′S)-N,N′-(1,3,4-oxadiazole-2,5-diylbis(4,1-phenyleneimino((2S)-1-oxo-1,2-propanediyl)))bis(2-hydroxy-2-phenylpropanamide);(2R,2′R)-N,N′-(1,3,4-oxadiazole-2,5-diylbis(4,1-phenyleneimino((2S)-1-oxo-1,2-propanediyl)))bis(2-hydroxy-2-phenylpropanamide);N,N′-(1,3,4-oxadiazole-2,5-diylbis(4,1-phenyleneimino((2S)-1-oxo-1,2-propanediyl)))bis(3-chloro-5-methoxy-l-isoquinolinecarboxamide);(2S,2′S)-N,N′-(1,3,4-oxadiazole-2,5-diylbis(4,1-phenyleneimino((2S)-1-oxo-1,2-propanediyl)))ditetrahydro-2-furancarboxamide;(2R,2′R)-N,N′-(1,3,4-oxadiazole-2,5-diylbis(4,1-phenyleneimino((2S)-1-oxo-1,2-propanediyl)))ditetrahydro-2-furancarboxamide;N,N′-(1,3,4-oxadiazole-2,5-diylbis(4,1-phenyleneimino((2S)-1-oxo-1,2-propanediyl)))bis(3-chloro-l-isoquinolinecarboxamide);N,N′-(1,3,4-oxadiazole-2,5-diylbis(4,1-phenyleneimino((2S)-1-oxo-1,2-propanediyl)))bis(4-chloro-2-pyridinecarboxamide);(2S,2′S)-N,N′-(1,3,4-oxadiazole-2,5-diyldi-4,1-phenylene)bis(2-(((2S)-2-(dimethylamino)-2-phenylacetyl)amino)propanamide);andN,N′-(1,3,4-oxadiazole-2,5-diylbis(4,1-phenyleneimino((2S)-1-oxo-1,2-propanediyl)))bis(2-chloro-6-methoxyisonicotinamide).14. A composition comprising a compound according to claim 1, or astereoisomer or a pharmaceutically acceptable salt or solvate thereof,and a pharmaceutically acceptable carrier.
 15. A method of treating anHCV infection in a patient, comprising administering to the patient atherapeutically effective amount of a compound according to claim 1, ora stereoisomer or a pharmaceutically acceptable salt or solvate thereof.